Surface treatment of contact lens and treatment of ocular discomfort by water soluble polymers and lipids/liposomes

ABSTRACT

Formulations (e.g., solutions) comprising one or more water-soluble polymer(s), liposomes, and an aqueous carrier, are provided. The provided solutions are useful for rinsing, and/or immersing therein, a contact lens and/or in the treatment of ocular discomfort, for example, an ocular discomfort associated with a contact lens. Also provided are kits comprising the solution and a contact lens; articles-of-manufacturing comprising the solution and configured for dispending the solution; and methods utilizing the solution.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.15/319,014 filed on Dec. 15, 2016, which is a National Phase of PCTPatent Application No. PCT/IL2015/050605 having International FilingDate of Jun. 15, 2015, which claims the benefit of priority under 35 USC§ 119(e) of U.S. Provisional Patent Application No. 62/012,379 filed onJun. 15, 2014. The contents of the above applications are allincorporated by reference as if fully set forth herein in theirentirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to materialscience and, more particularly, but not exclusively, to solutions,articles, and/or kits, and uses thereof in surface treatment of contactlens and/or in the treatment of ocular discomfort.

Soft contact lenses are typically made of hydrogels having varying watercontent (e.g., from 30% to 70% wt. water). Contact lenses are widelyused world-wide; globally there are over 100 million users, and theannual market value is estimated to be 7.6 billion USD. However, despitethe use of hydrogels which are compatible with the eye, many usersreport extensive eye irritation which prevents them using such lensesfor extended periods, or at all.

Many contact lens users report ocular discomfort that is attributed todryness, e.g., dry eye symptoms. It has been assumed that ocular comfortis related, among other factors, to friction at the eye/lensinterfaces—the interaction of the anterior surface of the contact lenswith the under surface of the eyelid, and its posterior interface withthe cornea—and several studies have accordingly been conducted in anattempt to better understand parameters that affect the sliding frictionforces of contact lenses [Rennie et al., Tribology Letters 2005,18:499-504; Roba et al., Tribology Letters 2011, 44:387-397; Ngai etal., Tribology and Interface Engineering Series, M. P. G. Dawson and A.A. Lubrecht, Editors. 2005, Elsevier. p. 371-379].

A review by Doughty [Contact Lens and Anterior Eye 1999, 22:116-126]describes various re-wetting, conform, lubricant and moisturizingsolutions and their potential impact on contact lens wearers. Many ofthe solutions described therein include polymers such ashydroxypropylmethylcellulose (HPMC; also known as hypromellose),hydroxyethylcellulose, carboxymethylcellulose, polyethylene glycol,poloxamer, polyvinylpyrrolidone (also known as povidone) and hyaluronicacid (HA).

Simmons et al. [CLAO J. 2001, 27:192-194] and Thai et al. [Ophthal.Physiol. Opt. 2002, 22:319-329] describe that the addition of the ocularlubricant HPMC to a multipurpose contact lens solution affect physicalproperties of the hydrogel lens surface and tear film production, andthereby improves wetting and ocular comfort. It has been reportedtherein that the multipurpose solution with HPMC produced a thick andlong-lasting layer of fluid on hydrogel lenses and other plastics, andthat HPMC was found to adsorb to and release gradually from contactlenses.

Hyaluronic acid (HA)—in the form of a 0.1% sodium hyaluronatesolution—is used as a contact lens lubricant in VisMed® Eye Drops[Doughty, Contact Lens and Anterior Eye 1999, 22:116-126]. HA-containingeye drops have been reported to be effective for reducing peripheralcorneal staining of rigid contact lens wearers [Itoi et al., CLAO J.1995, 21:261-264].

Davitt et al. [Journal of Ocular Pharmacology and Therapeutics 2010,26:347-353] and Benelli [Clinical Ophthalmology 2011, 5:783-790]describe that management of dry eye was achieved by a formulation ofpolyethylene glycol 400/propylene glycol-based lubricant eye dropscontaining hydroxypropyl guar as a gelling agent.

Surface modification of contact lenses has also been studied as a meansof reducing ocular discomfort.

Fakes et al., [Surface and Interface Analysis 1987, 10:416-423] haveused plasma charge treatment for surface modification of alkylacrylate/poly-siloxane co-polymer, in order to enhance surfacehydrophilicity, and hence wettability of the contact lens material.

Chen et al. [Biomaterials 2005, 26:2391-2399] describe surfacemodification of polydimethylsiloxane (a material used in contact lenses)by covalent immobilization of poly(ethylene oxide), for the purpose ofreducing protein adsorption.

International Patent Application publication WO 2014/071132 describes acontact lens coupled at its surface to a hyaluronic acid-bindingpeptide, for providing hyaluronic acid to the ocular environment bypretreating the lens with hyaluronic acid and replenishing hyaluronicacid from endogenous or exogenous sources as it is washed away ordegraded.

Liposomes are vesicles whose membranes in most cases are based onphospholipid bilayers. They are generally biocompatible and, whenmodified with other molecules, are widely used in clinical applications,primarily as drug delivery vehicles, as well as in gene therapy and fordiagnostic imaging.

Studies on surface lubrication by liposomes are described in, forexample, International Patent Application Publications WO 2008/038292and WO 2011/158237, Gaisinskaya et al. [Faraday Discuss. 2012,156:217-233], Goldberg et al. [Advanced Materials 2011, 23:3517-3521],Goldberg et al. [Chemistry and Physics of Lipids 2012, 165:374-381] andGoldberg et al. [Biophys. J. 2011, 100:2403-2411].

The mechanism of hydration lubrication, whereby hydration layers held bysurrounding charges provide effective boundary lubrication even at highpressures, is reviewed by Klein [Friction 2013, 1:1-23].

Gulsen et al. [Current Eye Research 2005, 30:1071-1080] teach contactlens compositions with drug delivery capabilities, and specificallyteach dispersing exceptionally small dimyristoylphosphatidylcholine(DMPC) SUV liposomes (less than 50 nm or 80 nm in diameter) in apoly-2-hydroxyethyl methacrylate (p-HEMA) hydrogel, a common contactlens material.

Nagarsenker et al. [International Journal of Pharmaceutics 1999,190:63-71] describe a use of neutral liposomes dispersed inpolycarbophil gel and positively charged liposomes as an ophthalmic drugdelivery system.

Additional background art includes U.S. Patent Application PublicationNos. 20040171740, 20060270781, 20100098749 and 20110293699; U.S. Pat.Nos. 7,638,137 and 8,273,366; Di Tizio et al. [Biomaterials, 1998, 19,p. 1877-1884]; Ludwig & van Ooteghem [J. Pharm. Belg. 1989, 44:391-397];Mourtas et al. [Langmuir 2009, 25:8480-8488]; Kang et al. [Journal ofDrug Targeting 2010, 18:637-644]; Pasquali-Ronchetti [Journal ofStructural Biology 1997, 120:1-10]; Sorkin et al. [Biomaterials 2103,34:5465-5475]; Berry et al. [Hyaluronan in dry eye and contact lenswearers. In: Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2, D. A.Sullivan, D. A. Dartt and M. A. Meneray, Editors. 1998, Plenum Press,NY, pp. 785-790]; and Brochu, Ph.D. Thesis in the Université deSherbrooke, Canada, 2008, Id.: 50177338.

SUMMARY OF THE INVENTION

According to an aspect of some embodiments of the present inventionthere is provided a solution comprising at least one water-solublepolymer, liposomes, and an aqueous carrier, the solution being for usein rinsing, and/or immersing therein, a contact lens.

According to an aspect of some embodiments of the present inventionthere is provided a solution comprising at least one water-solublepolymer, liposomes, and an aqueous carrier, the solution being for usein the treatment of ocular discomfort.

According to some of any of the embodiments described herein, the oculardiscomfort is associated with a contact lens.

According to some of any of the embodiments described herein, the atleast one water-soluble polymer comprises a non-ionic polymer.

According to some of any of the embodiments described herein, thenon-ionic polymer is selected from the group consisting of apolyvinylpyrrolidone and a polyethylene glycol.

According to some of any of the embodiments described herein, the atleast one water-soluble polymer comprises an ionic polymer.

According to some of any of the embodiments described herein, the ionicpolymer has from 1 to 6 charged groups per 1 kDa.

According to some of any of the embodiments described herein, the ionicpolymer is an anionic polymer.

According to some of any of the embodiments described herein, theanionic polymer is hyaluronic acid.

According to some of any of the embodiments described herein, theliposomes are characterized by a surface charge having a sign opposite asign of a net charge of the ionic polymer.

According to some of any of the embodiments described herein, the atleast one water-soluble polymer comprises a biopolymer.

According to some of any of the embodiments described herein, thebiopolymer is selected from the group consisting of a mucin, a lubricinand a polysaccharide.

According to some of any of the embodiments described herein, a molarpercentage of phosphatidylcholine in the liposomes is at least 50%.

According to some of any of the embodiments described herein, aconcentration of phospholipids of the liposomes in the solution is in arange of from 0.5 mM to 500 mM.

According to some of any of the embodiments described herein, theliposomes are selected from the group consisting of small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.

According to some of any of the embodiments described herein, theliposomes comprise multilamellar vesicles.

According to some of any of the embodiments described herein, theliposomes comprise small unilamellar vesicles.

According to some of any of the embodiments described herein, aviscosity of the solution is no more than 1000 cP.

According to some of any of the embodiments described herein, thecarrier is an ophthalmically acceptable carrier.

According to an aspect of some embodiments of the present inventionthere is provided an article-of-manufacturing comprising the solution asdescribed herein in any one of the embodiments thereof and anycombination of these embodiments, packaged in a container, the containerbeing configured for dispensing the solution.

According to some of any of the embodiments described herein, thecontainer is configured for dispensing a predetermined volume of thesolution.

According to an aspect of some embodiments of the present inventionthere is provided a kit comprising at least one contact lens and thesolution as described herein in any one of the embodiments thereof andany combination of these embodiments,

According to some of any of the embodiments described herein, the atleast one contact lens and the solution are packaged separately.

According to some of any of the embodiments described herein, thesolution is separately packaged in a container configured for dispensingthe solution.

According to some of any of the embodiments described herein, thecontact lens is immersed in a solution selected from the solution of anyone of claims 1 to 19 and an aqueous solution other than the solution ofany one of claims 1 to 19.

According to some of any of the embodiments described herein, thecontact lens is immersed in the solution.

According to an aspect of some embodiments of the present inventionthere is provided a method of treating ocular discomfort in a subject inneed thereof, the method comprising ophthalmically administering to thesubject an effective amount of the solution as described herein in anyone of the embodiments thereof and any combination of these embodiment.

According to some of any of the embodiments described herein, the oculardiscomfort is associated with a contact lens.

According to some of any of the embodiments described herein, thecontact lens comprises a hydrogel surface.

According to some of any of the embodiments described herein, thehydrogel comprises a polymer selected from the group consisting ofpoly(2-hydroxyethyl methacrylate) and a silicone.

According to some of any of the embodiments described herein, thehydrogel comprises a silicone.

According to some of any of the embodiments described herein, thehydrogel comprises a polymer having no more than one negatively chargedgroup per 2 kDa.

According to some of any of the embodiments described herein, thecontact lens comprises a surface which is positively charged orneutrally charged.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIGS. 1A-1B present photographs of a cornea-mimicking lens holder (FIG.1A) and the same holder with a soft contact lens mounted in place (FIG.1B), used in some of the experiments employing a tribometer described inthe Examples section hereinunder.

FIG. 2 presents bar graphs showing the friction coefficient of EtafilconA contact lens upon immersion in saline, HA 1 MDa 0.2 mg/ml, MLV HSPCliposomes (45 mM), MLV HSPC liposomes+HA, MLV DMPC (45 mM), or MLVDMPC+HA, followed by rinsing with saline, as measured at a load of 5, 10and 40 grams (corresponding respectively to mean pressures of 0.14, 0.17and 0.27 atmospheres).

FIG. 3 presents bar graphs showing the friction coefficient ofNarafilcon A contact lens upon immersion in saline, HA 1 MDa 0.2 mg/ml,MLV HSPC liposomes (45 mM), MLV HSPC liposomes+HA, MLV DMPC (45 mM), orMLV DMPC+HA, followed by rinsing with saline, as measured at a load of5, 10 and 40 grams (corresponding respectively to mean pressures of0.23, 0.29 and 0.46 atmosphere).

FIG. 4 presents bar graphs showing the friction coefficient of EtafilconA contact lens upon immersion in PBS, solutions of HA, PVP or PEO (0.2mg/ml), a solution of SUV DMPC liposomes (10 mM), or solutions of SUVDMPC liposomes with HA, PVP or PEO, followed by rinsing with PBS, asmeasured at a load of 3 and 10 grams (corresponding respectively to meanpressures of 0.1 and 0.16 atmospheres).

FIG. 5 presents bar graphs showing the friction coefficient of EtafilconA contact lens upon immersion in PBS, solutions of HA or PVP (0.2mg/ml), a solution of SUV HSPC liposomes (10 mM), or solutions of SUVHSPC liposomes with HA or PVP, followed by rinsing with PBS, as measuredat a load of 3 and 10 grams (corresponding respectively to meanpressures of 0.1 and 0.16 atmospheres).

FIG. 6 presents bar graphs showing the friction coefficient ofNarafilcon A contact lens upon immersion in PBS, solutions of HA or PVP(0.2 mg/ml), a solution of SUV DMPC liposomes (10 mM), or solutions ofSUV DMPC liposomes with HA or PVP, followed by rinsing with PBS, asmeasured at a load of 3 and 10 grams (corresponding respectively to meanpressures of 0.18 and 0.26 atmospheres).

FIG. 7 presents bar graphs showing the friction coefficient ofNarafilcon A contact lens upon immersion in PBS, solutions of HA, PVP orPEO (0.2 mg/ml), a solution of SUV HSPC liposomes (10 mM), or solutionsof SUV HSPC liposomes with HA, PVP or PEO, followed by rinsing with PBS,as measured at a load of 3 and 10 grams (corresponding respectively tomean pressures of 0.18 and 0.26 atmospheres).

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to materialscience and, more particularly, but not exclusively, to solutions,articles, and/or kits, and uses thereof in surface treatment of contactlens and/or in the treatment of ocular discomfort.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

In a search for an improved methodology for treating ocular discomfortand/or preventing ocular discomfort frequently associated with usingcontact lens, the present inventors have studied the effect of asolution containing liposomes, particularly phosphatidylcholine(PC)-containing liposomes, which are known to be biocompatible, incombination with various water-soluble polymers, while using differenttypes of commercially available contact lens, under ocular conditions,and have surprisingly uncovered that this combination considerablyexceeds the lubrication effect observed in the presence of liposomesalone or the water-soluble polymers alone, resulting in a synergisticeffect in reducing the friction coefficient of the tested contact lens.The lubrication effect is mediated by boundary lubrication, that is, itdoes not require the presence of the solution between the contact lensand ocular surface. Rather, contact with the solution results in atreated contact lens surface, wherein the surface per se ischaracterized by enhanced lubricity.

Referring now to the drawings, FIGS. 2 and 3 show that exposure ofcontact lenses composed of etafilcon A (FIG. 2) and narafilcon A (FIG.3) hydrogels to liposomes (multilamellar vesicles) and hyaluronic acid(HA) enhances the lubricity of the contact lenses more effectively thandoes exposure to liposomes alone or HA alone (as determined using thecornea model shown in FIGS. 1A-1B). FIGS. 4-7 show that exposure ofcontact lenses composed of etafilcon A (FIGS. 4 and 5) and narafilcon A(FIGS. 6 and 7) hydrogels to liposomes (small unilamellar vesicles) andhyaluronic acid (HA), polyvinylpyrrolidone (PVP) or polyethylene oxide(PEO) enhances the lubricity of the contact lenses more effectively thandoes exposure to liposomes alone or HA, PVP or PEO, and that PVP and PEOare typically at least as effective as HA at enhancing lubricity incombination with liposomes. FIGS. 4 and 7 show that PEO exhibitsparticularly strong synergy with liposomes at enhancing lubricity,whereas PEO alone does not enhance lubricity at all and may even reducelubricity.

This result surprisingly indicates that a contact lens surface contactedwith a water-soluble polymer (such as HA, PVP or PEO) and liposomes isnot a mosaic of a surface coated by water-soluble polymer per se and asurface coated by liposomes per se (which would result in a lubricitywhich is intermediate between the lubricity obtained with water-solublepolymer alone and with liposomes alone), but rather, a surface coatedwith water-soluble polymer and liposomes exhibits a physicalcharacteristic which is not present in surfaces coated by water-solublepolymer alone or liposomes alone, indicating synergy between thewater-soluble polymer and liposomes.

FIGS. 2-7 further show that at relatively low pressures dimyristoylphosphatidylcholine liposomes (which are in a liquid phase) are moreeffective at reducing the lubricity than are hydrogenated soyphosphatidylcholine liposomes (which are in a solid phase), whereas athigher pressures, hydrogenated soy phosphatidylcholine liposomes aremore effective.

Without being bound by any particular theory, it is believed that theamphiphilic lipids supplied by the liposomes provide a very low frictioncoefficient as a result of hydration lubrication associated withhydration of the hydrophilic moieties of the lipids. It is furtherbelieved that attachment of a water-soluble polymer to a lens surface(e.g., by adsorption) enhances lubricity by facilitating adherence ofthe lubricating lipids to the surface (e.g., anchoring the lipids to thesurface), particularly to a lens surface which does not normally exhibitaffinity to such lipids, thereby enhancing the robustness of thelubricating lipid film.

Without being bound by any particular theory, it is further believedthat attachment of the water-soluble polymer to a lens surface mayresult in a smoother surface (e.g., by covering asperities with flexiblepolymer chains thereby further enhancing lubricity).

Based on the results presented herein, lubrication of a contact lens-eyeinterface may be effected, in accordance with various embodiments of theinvention described herein.

According to an aspect of some embodiments of the invention, there isprovided a formulation comprising at least one water-soluble polymer (asdefined herein in any one of the respective embodiments), liposomes (asdefined herein in any one of the respective embodiments), and an aqueouscarrier, the solution being for use in rinsing and/or immersing thereina contact lens.

According to an aspect of some embodiments of the invention, there isprovided a formulation comprising at least one water-soluble polymer (asdefined herein in any one of the respective embodiments), liposomes (asdefined herein in any one of the respective embodiments), and an aqueouscarrier, the solution being for use in treatment of ocular discomfort.

The formulation, according to any of the aspects described herein, mayoptionally comprise at least one water-soluble polymer, liposomes andcarrier according to any one of the embodiments described hereinrelating to water-soluble polymer(s) (e.g., in the section hereinrelating to water-soluble polymers), liposomes and lipids (e.g., in thesection herein relating to liposomes and lipids), aqueous carrier and/orany combination thereof.

In some of any of the embodiments described herein, the formulation is aliquid formulation, and is also referred to herein interchangeably as“solution”. It is to be noted that herein throughout, the term“solution” encompasses any liquid formulation in which the ingredients,namely, at least the water-soluble polymer and the liposomes/lipids areincluded within a liquid carrier, whereby each of the ingredients can bedissolved or dispersed within the carrier. The term “solution” as usedherein therefore encompasses also “dispersion”. The term “liquidformulation” as used herein encompasses both a solution and adispersion.

As used herein, the term “rinsing” generally refers to brief contact(e.g., for several seconds) with a liquid (e.g., the solution describedherein), whereas the term “immersing” generally refers to longer periodsof contact with a liquid (e.g., the solution described herein). However,both terms refer to contact with a liquid, and are typically used hereintogether to encompass all forms of contact with a liquid, for example,in embodiments wherein the difference between rinsing and immersing isof no particular significance.

Without being bound by any particular theory, it is believed thatrinsing and/or immersing a contact lens in a solution described hereincan reduce a friction coefficient of a contact lens surface (e.g., thesurface intended to be in contact with the eye and/or the surfaceintended to face the eyelid), thereby reducing discomfort and/orirritation associated with the contact lens in many users.

Without being bound by any particular theory, it is further believedthat the solutions described herein are particularly suitable forcontact with physiological surfaces such as the eye and surfaces (e.g.,contact lens surfaces) which come into contact with physiologicalsurfaces, because the liposomes and water-soluble polymer(s) may readilybe selected so as to be biocompatible, optionally even be selected assubstances naturally occurring in the body, and because hydrationlubrication mechanism (e.g., as described herein in any one of therespective embodiments) is fully compatible with aqueous environmentssuch as physiological environments, as opposed, for example, tolubrication via non-aqueous liquid lubricants (e.g., oils).

In some embodiments of any one of the embodiments described hereinrelating to ocular discomfort, the ocular discomfort is associated witha contact lens. Association of a contact lens with ocular discomfort maybe based on an observation of a contact lens wearer, for example, thatdiscomfort occurs when contact lens are being worn, and/or based on adiagnosis by a physician (e.g., ophthalmologist), for example, that anocular discomfort (e.g., chronic discomfort) is caused by a contactlens.

In some embodiments according to any of the aspects described hereinrelating to a contact lens surface, the liposomes are selected such thatthe lipids on a contact lens surface are in a liquid phase when thecontact lens is worn.

Without being bound by any particular theory, it is believed that lipidsin a liquid phase are more effective than lipids in a solid phase atreducing a friction coefficient of the surface, and that the superiorrobustness of the solid phase is not particularly advantageous in thecontext of contact lenses, which are generally not subjected to highpressures. However, lipids in a solid phase can also be highlyeffective, as exemplified herein in the Examples section.

In some embodiments of any one of the embodiments described herein, theliposomes are characterized by a phase transition melting point (Tm)below 37° C. In some embodiments, the Tm is below 36° C. In someembodiments, the Tm is below 35° C. In some embodiments, the Tm is below34° C. In some embodiments, the Tm is below 32° C. In some embodiments,the Tm is below 30° C. In some embodiments, the Tm is below 25° C. Insome embodiments, the Tm is below 20° C.

According to another aspect of embodiments of the invention, there isprovided a method of treating ocular discomfort in a subject in needthereof, the method comprising ophthalmically administering to thesubject an effective amount of the solution comprising liposomes andwater-soluble polymer(s), as described herein in any one of therespective embodiments. In some embodiments, the ocular discomfort isassociated with a contact lens, as described herein in any one of therespective embodiments.

According to another aspect of embodiments of the invention, there isprovided a use of the solution comprising liposomes and water-solublepolymer(s), as described herein in any one of the respectiveembodiments, in the manufacture of a medicament for treating oculardiscomfort. In some embodiments, the ocular discomfort is associatedwith a contact lens, as described herein in any one of the respectiveembodiments.

It is expected that during the life of a patent maturing from thisapplication many relevant contact lens, hydrogels for forming contactlens, and liposomes will be developed and the scope of the terms“contact lens” and “liposomes” is intended to include all such newtechnologies a priori.

Liposomes and Lipids:

The liposomes and/or lipids according to any one of the embodimentsdescribed in this section may be used in the context of any one of theembodiments of any of the aspects of the inventions described herein.

As used herein and in the art, the term “liposome” refers to anartificially prepared vesicle comprising a bilayer composed of moleculesof an amphiphilic lipid. In an aqueous medium, the bilayer is typicallyconfigured such that hydrophilic moieties of the amphiphilic lipid areexposed to the medium at both surfaces of the bilayer, whereaslipophilic moieties of the lipid are located in the internal portion ofthe bilayer, and therefore less exposed to the medium. Examples ofliposomes which may be used in any one of the embodiments describedherein include, without limitation, small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles.

In some embodiments of any one of the embodiments described herein, theliposomes comprise multilamellar vesicles. In some embodiments, theliposomes are primarily (more than 50 weight percents) multilamellarvesicles.

In some embodiments of any one of the embodiments described herein, theliposomes comprise small unilamellar vesicles. In some embodiments, theliposomes are primarily (more than 50 weight percents) small unilamellarvesicles.

In some embodiments of any one of the embodiments described herein, theliposomes comprise large unilamellar vesicles. In some embodiments, theliposomes are primarily (more than 50 weight percents) large unilamellarvesicles.

As used herein, the term “unilamellar” refers to liposomes characterizedby a single lipid bilayer, whereas the term “multilamellar” refers toliposomes characterized by a multiple lipid bilayers, for example,concentric bilayers.

As used herein, the phrase “small unilamellar vesicle” refers tounilamellar liposomes of less than 100 nm in diameter, whereas thephrase “large unilamellar vesicle” refers to unilamellar liposomes atleast 100 nm in diameter.

As used herein, the term “amphiphilic lipid” refers to compoundscomprising at least one hydrophilic moiety and at least one lipophilicmoiety. Examples of amphiphilic lipids include, without limitation,fatty acids (e.g., at least 6 carbon atoms in length) and derivativesthereof such as phospholipids and glycolipids; sterols (e.g.,cholesterol) and steroid acids.

Herein, the term “phospholipid” refers to a compound comprising asubstituted or non-substituted phosphate group and at least one alkylchain (optionally at least two alkyl chains) which is optionally atleast 5 carbon atoms in length, optionally at least 7 atoms in lengthand optionally at least 9 atoms in length. The at least one alkyl chainis optionally a part of an acyl group (e.g., a fatty acid residue) or analkyl group per se (e.g., a fatty alcohol residue). In some embodiments,the phosphate group and on e or two (optionally two) alkyl chains (e.g.,acyl or alkyl) are attached to a glycerol moiety via the oxygen atoms ofglycerol.

In some embodiments of any one of the embodiments described herein, theamphiphilic lipids coating a surface and/or substrate described herein(e.g., a contact lens surface, a physiological surface, and/or a surfacewhose friction coefficient is being reduced, according to any one of therespective embodiments described herein) are in the form of intactliposomes, optionally essentially the same liposomes (e.g., essentiallythe same mass and molecular composition) contacted with thewater-soluble polymer(s).

In some embodiments of any one of the embodiments described herein, atleast a portion of the amphiphilic lipids (optionally substantially allof the lipids) coating the surface are in a form substantially differentthan the liposomes from which the lipids are derived. In someembodiments, during the coating for the surface, liposomes are convertedto open layers (e.g., lipid bilayers and/or lipid monolayers), asopposed to the closed vesicular structure of the liposomes.

Accordingly, any reference herein to coating a surface with liposomesshould not be interpreted as meaning that an obtained coated surfacecomprises liposomes, only that liposomes are utilized by the methodology(e.g., as an ingredient).

As used herein, the term “phospholipid” encompasses lipids having a(phosphorylated) glycerol backbone (e.g., monoacylglyceride and/ordiacylglyceride phospholipids), referred to as glycerophospholipids; andlipids having a (phosphorylated) sphingosine backbone, referred to asphosphosphingolipids (e.g., sphingomyelins).

As used herein, the term “glycolipid” encompasses lipids having a(glycosylated) glycerol backbone (e.g., monoacylglyceride and/ordiacylglyceride glycolipids), referred to as glyceroglycolipids; andlipids having a (glycosylated) sphingosine backbone, referred to asglycosphingolipids (e.g., cerebrosides, gangliosides).

In some embodiments of any one of the embodiments described herein, thehydrophilic moiety is an ionic moiety.

Herein, the phrase “ionic moiety” refers to a moiety which comprises atleast one charged group (as defined herein), and includes anionicmoieties (which have a net negative charge), cationic moieties (whichhave a net positive charge) and zwitterionic moieties (which have anequal number of positive and negative charges, and thus, no net charge).

Without being bound by any particular theory, it is believed that ionicmoieties are particularly effective at binding to water molecules, whichrenders lipid molecules comprising such moieties particularly effectiveat promoting hydration lubrication, in which the bound water moleculesprovide lubrication even at high pressures.

In some embodiments of any one of the embodiments described herein, theamphiphilic lipid comprises at least one phospholipid. Phospholipids aretypically characterized by the presence of an ionic moiety whichincludes a negative charge associated with an oxygen atom in a phosphatemoiety (P—O⁻), although additional charges may be present.

In some embodiments of any one of the embodiments described herein, thephospholipid is a glycerophospholipid. In some embodiments, theglycerophospholipid is a diacylglyceride, comprising two fatty acylgroups and one phosphate group attached to a glycerol backbone.

In some embodiments of any one of the embodiments described herein, aconcentration of phospholipids in liposomes in a solution describedherein is in a range of from 0.5 mM to 500 mM. In some embodiments, theconcentration is in a range of from 1.5 mM to 150 mM. In someembodiments, the concentration is in a range of from 5 mM to 50 mM.

In some embodiments of any one of the embodiments described herein, aconcentration of phospholipids in liposomes in a solution describedherein is in a range of from 0.5 mM to 50 mM. In some embodiments, theconcentration is in a range of from 1.5 mM to 50 mM.

In some embodiments of any one of the embodiments described herein, aconcentration of phospholipids in liposomes in a solution describedherein is in a range of from 5 mM to 500 mM. In some embodiments, theconcentration is in a range of from 5 mM to 150 mM.

In some embodiments of any one of the embodiments described herein, theamphiphilic lipid comprises at least one negatively charged atom and atleast one positively charged atom. In some embodiments, the amphiphiliclipid is zwitterionic, that is, the one or more negative charges in themolecule are balanced out by an equal number of positive charge(s) inthe molecule. In some embodiments, the amphiphilic lipid comprisesexactly one negative charge and one positive charge.

In some embodiments of any one of the embodiments described herein, theamphiphilic lipid comprises at least one phospholipid which comprises aphosphoethanolamine group or N-alkyl derivative thereof.

The phrase “phosphoethanolamine group or N-alkyl derivative thereof”refers to a —O—P(═O)(—O⁻)—OCH₂CH₂NR′R″R′″⁺ group (or a salt thereof),wherein R′, R″ and R′″ are each independently hydrogen or alkyl,preferably C₁₋₄ alkyl. In some embodiments of any one of the embodimentsdescribed herein, the alkyl group(s) attached to the nitrogen atom areeach independently methyl or ethyl. In some embodiments, the alkyl(s) ismethyl. The term “phosphoethanolamine” refers to a group wherein R′, R″and R′″ are each hydrogen. The term “phosphocholine” refers to a groupwherein R′, R″ and R′″ are each methyl.

Without being bound by any particular theory, it is believed that thedistance between the positive and negative charges in aphosphoethanolamine group or N-alkyl derivative thereof is particularlysuitable for binding water molecules and/or promoting hydrationlubrication.

In some embodiments of any one of the embodiments described herein, amolar percentage of the phospholipid described herein (e.g., inliposomes described herein) which comprises a phosphoethanolamine groupor N-alkyl derivative thereof is at least 20%. In some embodiments, themolar percentage is at least 40%. In some embodiments, the molarpercentage is at least 50%. In some embodiments, the molar percentage isat least 60%. In some embodiments, the molar percentage is at least 70%.In some embodiments, the molar percentage is at least 80%. In someembodiments, the molar percentage is at least 90%. In some embodiments,the phospholipid consists essentially of at least one phospholipidcomprising a phosphoethanolamine group or N-alkyl derivative thereof.

In some embodiments of any one of the embodiments described herein, amolar percentage of the amphiphilic lipid described herein (e.g., inliposomes described herein) which consists of at least one phospholipidwhich comprises a phosphoethanolamine group or N-alkyl derivativethereof is at least 20%. In some embodiments, the molar percentage is atleast 40%. In some embodiments, the molar percentage is at least 50%. Insome embodiments, the molar percentage is at least 60%. In someembodiments, the molar percentage is at least 70%. In some embodiments,the molar percentage is at least 80%. In some embodiments, the molarpercentage is at least 90%. In some embodiments, the amphiphilic lipidconsists essentially of at least one phospholipid which comprises aphosphoethanolamine group or N-alkyl derivative thereof.

In some embodiments of any one of the embodiments described herein, theat least one phospholipid comprises at least one phosphatidylcholine.

Herein and in the art, the term “phosphatidylcholine” refers to aglycerophospholipid comprising a phosphocholine group and two fatty acylgroups attached to a glycerol backbone (i.e., a diacylglyceride).

In some embodiments of any one of the embodiments described herein, thephospholipid described herein (e.g., in liposomes described herein) ischaracterized by a molar percentage of phosphatidylcholine (the at leastone phosphatidylcholine described herein) which is at least 20%. In someembodiments, the molar percentage is at least 40%. In some embodiments,the molar percentage is at least 50%. In some embodiments, the molarpercentage is at least 60%. In some embodiments, the molar percentage isat least 70%. In some embodiments, the molar percentage is at least 80%.In some embodiments, the molar percentage is at least 90%. In someembodiments, the phospholipid consists essentially of at least onephosphatidylcholine.

In some embodiments of any one of the embodiments described herein, theamphiphilic lipid described herein (e.g., in liposomes described herein)is characterized by a molar percentage of phosphatidylcholine (the atleast one phosphatidylcholine described herein) which is at least 20%.In some embodiments, the molar percentage is at least 40%. In someembodiments, the molar percentage is at least 50%. In some embodiments,the molar percentage is at least 60%. In some embodiments, the molarpercentage is at least 70%. In some embodiments, the molar percentage isat least 80%. In some embodiments, the molar percentage is at least 90%.In some embodiments, the amphiphilic lipid consists essentially of atleast one phosphatidylcholine.

The fatty acyl groups in a lipid described herein may comprise saturatedfatty acyl groups, monounsaturated fatty acyl groups (having a singleunsaturated bond) and/or polyunsaturated fatty acyl groups (having twoor more unsaturated bonds). In some embodiments, the unsaturated bondsare cis double bonds.

Examples of suitable saturated fatty acyl groups include, withoutlimitation, lauroyl, myristoyl, palmitoyl and stearoyl.

Examples of suitable monounsaturated fatty acyl groups include, withoutlimitation, oleoyl, palmitoleoyl, eicosenoyl, erucoyl, nervonoyl andvaccenoyl.

Examples of suitable polyunsaturated fatty acyl groups include, withoutlimitation, linoleoyl, α-linolenoyl, γ-linolenoyl, dihomo-γ-linolenoyl,stearidonoyl, eicosatetraenoyl, eicosapentaenoyl, docosapentaenoyl,docosahexaenoyl, arachidonoyl and adrenoyl.

In some embodiments of any one of the embodiments described herein, thefatty acyl groups are selected from the group consisting of saturatedand monounsaturated fatty acyl groups. In some embodiments, the fattyacyl groups are saturated fatty acyl groups.

Without being bound by any particular theory, it is believed thatsaturated and monounsaturated fatty acyl groups, particularly saturatedfatty acyl groups, are relatively resistant to chemical reaction such asoxidation, and therefore provide a more resilient system.

In some embodiments of any one of the embodiments described herein, atleast 50% of the fatty acyl groups are the same species of fatty acylgroup (e.g., myristoyl, palmitoyl). In some embodiments, at least 75% ofthe fatty acyl groups are the same species of fatty acyl group. In someembodiments, at least 90% of the fatty acyl groups are the same speciesof fatty acyl group.

Exemplary phospholipids comprising a single species of fatty acyl groupinclude 1,2-dimyristoyl-sn-glycero-3-phosphocholine and1,2-dipalmitoyl-sn-glycero-3 phosphocholine.

It is to be appreciated that phase transitions, e.g., melting points(Tm), of the lipid bilayers and liposomes described herein may bedetermined by the skilled person by selecting suitable fatty acyl groupsfor inclusion in the lipids, for example, by selecting relatively shortand/or unsaturated fatty acyl groups (e.g., myristoyl) to obtain arelatively low melting point; and/or by selecting relatively long and/orsaturated fatty acyl groups (e.g., palmitoyl and/or stearoyl) to obtaina relatively high melting point.

In some embodiments of any one of the embodiments described herein, theliposomes described herein are characterized by a phase transitionmelting point above an expected ambient temperature of a surface towhich the liposomes are applied (e.g., as described herein in any one ofthe respective embodiments), such that a surface coated by lipids at theexpected ambient temperature will be coated predominantly by lipids in asolid phase. For example, in some embodiments, liposomes characterizedby a melting point above a physiological temperature (e.g., about 37°C.) are used to coat a physiological surface with lipids (e.g., asdescribed herein in any one of the respective embodiments).

Without being bound by any particular theory, it is believed that lipidcoatings in a solid phase are more resilient than lipid coatings in aliquid phase, and are therefore particularly suitable for providinglubrication to surfaces for a prolonged period of time and/or surfaces(e.g., articular surfaces of joints) subject to high pressures (e.g., 10atmospheres or more).

In some embodiments of any one of the embodiments described herein, theliposomes described herein are characterized by a phase transitionmelting point below an expected ambient temperature of a surface towhich the liposomes are applied (e.g., as described herein in any one ofthe respective embodiments), such that a surface coated by lipids at theexpected ambient temperature will be coated predominantly by lipids in aliquid phase. For example, in some embodiments, liposomes characterizedby a melting point below a physiological temperature (e.g., about 36°C.) are used to coat a physiological surface with lipids (e.g., asdescribed herein in any one of the respective embodiments).

Without being bound by any particular theory, it is believed that lipidcoatings in a liquid phase provide the most effective lubrication at lowpressures (e.g., below 10 atmospheres) where a particularly prolongedperiod of life-time is not crucial, and are therefore particularlysuitable for providing lubrication to surfaces (e.g., contact lenssurfaces) which are generally not subjected to such high pressures andwhich may be readily replaced (e.g., as in disposable contact lenses)and/or re-coated with a lipid.

In some embodiments of any one of the embodiments described herein, theliposomes described herein are characterized by a surface charge, whichmay be a positive surface charge or a negative surface charge.

As used herein, the phrase “surface charge” refers to an electric chargeat or near a surface, such as an interface of a liposome with asolution. The phrase “surface charge” encompasses an electric chargeassociated with an electric potential at a surface (e.g., such that apositive electric potential at a surface is indicative of a positivesurface charge, whereas a negative electric potential at a surface isindicative of a negative surface charge); as well as an electric chargewhich is closer to a surface than an electric charge of an opposite sign(e.g., as in a zwitterion wherein the positive charge is closer to thesurface than the negative charge, or vice versa), such that an ion nearthe surface will interact primarily with the electric charge near thesurface (due to the proximity) as opposed to the electric charge of anopposite sign. For example, phosphatidylcholine liposomes typicallyexhibit a positive surface charge because the positive charge of thecholine group is closer to the liposome surface than the negative chargeof the phosphate group.

Optionally, a surface charge of a liposome is associated with a netcharge of the lipid molecules in the liposome, for example, a liposomecomprising anionic lipids has a negative surface charge, and/or aliposome comprising cationic lipids has a positive surface charge.

Alternatively or additionally, a surface charge of a liposome isassociated with a dipole of lipid molecules (e.g., zwitterionic lipidmolecules) in the liposome, for example, a liposome comprising azwitterionic lipid comprising a phosphocholine group may have a positivesurface charge due to the positively charged ammonium groups in thephosphocholine groups being (on average) closer to the surface of theliposomes than the negatively charged phosphate groups in thephosphocholine groups.

The skilled person will be readily capable of determining a surfacecharge. For example, the sign of a surface charge may be determined bycomparing the propensity of a surface (e.g., of a liposome) to bind toanionic vs. cationic compounds (e.g., labeling compounds).Alternatively, or in addition, surface charge can be determined by zetapotential measurements, using techniques well known in the art.

In some embodiments of any one of the embodiments described herein, theliposomes rupture upon contact with the water-soluble polymer(s) (e.g.,on a surface). Liposome rupture may optionally result in a lipid bilayerin the liposomes being converted from a curved geometry (e.g., as in therelatively spherical liposomes) to a flatter geometry which complementsthe geometry of the surface and/or the water-soluble polymer(s) attachedto the surface (e.g., thereby enhancing affinity of the lipids to thesurface); and/or which results in a flatter, smoother lipid-coatedsurface (e.g., thereby further reducing friction).

Without being bound by any particular theory, it is believed thatrupture of liposomes is induced by affinity of the surface-attachedwater-soluble polymer(s) to the lipids in the liposome, whereby ruptureof the liposomes allows a greater area of the surface-attachedwater-soluble polymer(s) to come into contact with lipids, therebyincreasing an amount of energetically favorable interactions between thewater-soluble polymer(s) and lipid.

In some embodiments of any one of the embodiments described herein,liposomes and water-soluble polymer(s) are selected such that theselected water-soluble polymer(s) is effective at rupturing the selectedliposomes.

Water-Soluble Polymer(s):

The water-soluble polymer(s) according to any one of the embodimentsdescribed in this section may be used in the context of any one of theembodiments of any of the aspects of the inventions described herein,and in combination with liposomes and/or lipids according to any one ofthe embodiments described herein with respect to liposomes and/orlipids.

As used herein, the phrase “water-soluble polymer” encompasses polymershaving a solubility of at least 1 gram per liter in an aqueous (e.g.,water) environment at pH 7 (at 25° C.).

In some embodiments of any of the embodiments described herein, thewater-soluble polymer has a solubility of at least 2 grams per liter(under the abovementioned conditions). In some embodiments, thesolubility is at least 5 grams per liter. In some embodiments, thesolubility is at least 10 grams per liter. In some embodiments, thesolubility is at least 20 grams per liter. In some embodiments, thesolubility is at least 50 grams per liter. In some embodiments, thesolubility is at least 100 grams per liter.

The water-soluble polymer(s) according to any pf the embodimentsdescribed herein may comprise at least one ionic polymer and/or at leastone non-ionic polymer which is water-soluble as defined herein.

As used herein, the phrase “non-ionic polymer” refers to a polymer whichdoes not have a charged group.

Examples of suitable non-ionic water-soluble polymers include, withoutlimitation, polyvinylpyrrolidone (also referred to hereininterchangeably as povidone and/or PVP) and polyethylene oxide (alsoreferred to herein interchangeably as PEO, PEG and/or polyethyleneglycol).

As used herein, the phrase “ionic polymer” refers to polymers having atleast one charged group, and encompasses polymers having a net negativecharge (also referred to herein as “anionic polymers”), polymers havinga net positive charge (also referred to herein as “cationic polymers”),and polymers having no net charge (also referred to herein as“zwitterionic polymers”), in an aqueous (e.g., water) environment at pH7.

Herein throughout, the phrase “charged group” refers to any functionalgroup (e.g., a functional group described herein) which is ionic (asdefined herein), including, for example, amine, carboxylic acid,sulfate, sulfonate, phosphate and phosphonate. Thus, each electriccharge in a moiety or molecule is associated with one charged group,although a single charged group (e.g., non-substituted phosphate) may beassociated with more than one electric charge of the same sign (e.g., adianion, a dication).

Herein throughout, the term “ionic” refers to the presence of anelectric charge on at least one atom in a moiety and/or molecule (in atleast 50% of moieties and/or molecules in a population) in an aqueousmedium (e.g., water) at pH 7. The electric charge may be negative(anionic) or positive (cationic). If more than one electric charge ispresent, the electric charges may be negative (anionic) and/or positive(cationic), for example, both a negative and a positive charge may bepresent (zwitterionic).

In some embodiments of any one of the embodiments described hereinrelating to an ionic polymer, at least 75% of the ionic groups in thepolymer have the same charge, that is, at least 75% of the ionic groupsare cationic groups or are anionic groups, such that the polymer issubstantially cationic or anionic, respectively. In some embodiments, atleast 90% of the ionic groups in the polymer have the same charge. Insome embodiments, at least 95% of the ionic groups in the polymer havethe same charge. In some embodiments, at least 98% of the ionic groupsin the polymer have the same charge. In some embodiments, at least 99%of the ionic groups in the polymer have the same charge.

In some embodiments of any one of the embodiments described herein,about 50% of the ionic groups in the polymer have a positive charge andabout 50% of the ionic groups in the polymer have a negative charge,such that the polymer is substantially zwitterionic.

In some embodiments of any one of the embodiments described herein, theionic polymer is characterized by a charge density of from 1 to 6charged groups (ionic groups) per 1 kDa molecular weight of the polymer.In some embodiments, the ionic polymer has from 1.5 to 4 charged groupsper 1 kDa. In some embodiments, the ionic polymer has from 2 to 3charged groups per 1 kDa.

In some embodiments of any one of the embodiments described herein, theionic polymer is characterized by a net charge (i.e., the differencebetween the number of anionic groups and the number of cationic groups)of from 1 to 6 electric charges per 1 kDa molecular weight of thepolymer. In some embodiments, the ionic polymer has a net charge of from1.5 to 4 charges per 1 kDa. In some embodiments, the ionic polymer has anet charge of from 2 to 3 charges per 1 kDa.

In some embodiments of any one of the embodiments described herein, theionic polymer is an anionic polymer, for example, a polymercharacterized by a net negative charge of from 1 to 6 electric chargesper 1 kDa molecular weight of the polymer.

In some embodiments of any one of the embodiments described herein, theionic polymer is a cationic polymer, for example, a polymercharacterized by a net positive charge of from 1 to 6 electric chargesper 1 kDa molecular weight of the polymer.

In some embodiments of any one of the embodiments described herein, theionic polymer is a polysaccharide (which is an ionic polysaccharide).

As used herein throughout, the term “polysaccharide” refers to a polymercomposed primarily (at least 50 weight percents) of monosaccharide unitslinked by glycosidic linkages.

As used herein, the term “monosaccharide” encompasses carbohydrates perse (having the formula Cn(H₂O)n, wherein n is at least 3, typically from3 to 10), as well as derivatives thereof such as amino sugars, in whichat least one hydroxyl group is replaced by an amine or amide group;sugar acids, in which one or two carbon atoms are oxidized to form acarboxylate group; acylated monosaccharides, in which at least onehydroxyl group and/or amine group is substituted by an acyl group (e.g.,acetyl); and sulfated monosaccharides, in which at least one hydroxylgroup is replaced by a sulfate group.

Examples of monosaccharides include, without limitation, hexoses (e.g.,D-hexoses and/or L-hexoses) such as allose, altrose, glucose, mannose,gulose, idose, galactose, talose, psicose, fructose, sorbose andtagatose; pentoses (e.g., D-pentoses and/or L-pentoses) such asarabinose, lyxose, xylose, ribose, ribulose and xylulose; and hexosederivatives such as glucuronic acid, iduronic acid, manuronic acid,guluronic acid, glucosamine and N-alkyl derivatives thereof,galactosamine and N-alkyl derivatives thereof, N-acetylglucosamine,N-acetylgalactosamine, and monosulfated and disulfatedN-acetylgalactosamine, glucuronic acid and iduronic acid.

As used herein, the phrase “glycosidic linkage” refers to a bond betweena hemiacetal group of one compound (e.g., a monosaccharide monomer) anda hydroxyl group of another compound (e.g., another monosaccharidemonomer).

Examples of ionic polysaccharides include, without limitation,hyaluronic acid, chondroitin sulfate, alginic acid, xanthan gum,chitosan and N-alkyl chitosan derivatives.

Hyaluronic acid is an anionic polysaccharide comprising anionicglucuronic acid monomer units along with non-ionic N-acetylglucosaminemonomer units. Hyaluronic acid is an exemplary anionic polymer.

Chondroitin sulfate is an anionic polysaccharide comprising anionicsulfated (e.g., monosulfated and/or disulfated) N-acetylgalactosamine,glucuronic acid and/or iduronic acid monomer units, and anionicglucuronic acid and/or iduronic acid monomer units, along with non-ionicN-acetylgalactosamine monomer units.

Alginic acid is an anionic polysaccharide comprising anionic mannuronicacid and guluronic acid monomer units.

Xanthan gum is an anionic polysaccharide comprising anionic glucuronicacid monomer units, along with non-ionic glucose and mannose monomerunits (including acetyl and/or pyruvyl derivatives thereof).

Chitosan is a cationic polysaccharide comprising cationic glucosaminemonomer units, optionally along with non-ionic N-acetylglucosaminemonomer units. In N-alkyl chitosan derivatives, at least a portion ofthe glucosamine units comprise 1, 2 or 3 alkyl groups, preferably C₁₋₄alkyl, attached to the nitrogen atom. In some embodiments of any one ofthe embodiments described herein, the alkyl groups attached to thenitrogen atoms are each independently methyl or ethyl. In someembodiments, the alkyls are methyl. In some embodiments, the N-alkylatedmonomer unit is N-trimethylglucosamine.

Herein, the terms “hyaluronic acid”, “chondroitin sulfate”, “alginicacid”, “xanthan gum”, “chitosan”, “N-alkyl chitosan derivatives” and anyother ionic compounds named herein, encompass all salts of the namedcompounds along with the non-ionic forms (e.g., acid forms of theanionic polysaccharides, and the free base forms of the cationicpolysaccharides).

Without being bound by any particular theory, it is believed thathyaluronic acid on a surface is particularly effective at binding toliposomes and rupturing them, thereby forming a lipid coating (e.g.,lipid bilayer) with relatively high affinity to a surface, such as acontact lens surface.

It is further believed that hyaluronic acid is particularly suitable foruse in the context of contact lenses, as hyaluronic acid is naturallypresent on the ocular surface.

In some embodiments of any one of the embodiments described herein, thepolysaccharide is in a form of a salt. In some embodiments, the salt isa pharmaceutically acceptable salt (e.g., an ophthalmically acceptablesalt for an ophthalmic application described herein, a salt suitable forparenteral administration for a parenteral application describedherein).

In some embodiments of any one of the embodiments described herein, thepolysaccharide has from 0.2 to 1 charged groups per monosaccharideresidue. In some embodiments, the polysaccharide has from 0.2 to 0.9charged groups per monosaccharide residue. In some embodiments, thepolysaccharide has from 0.3 to 0.7 charged groups per monosaccharideresidue. In some embodiments, the polysaccharide has from 0.4 to 0.6charged groups per monosaccharide residue. In some embodiments, thepolysaccharide has about 0.5 charged groups per monosaccharide residue.

It is to be appreciated that a monosaccharide residue may comprise morethan one charged group (e.g., a sulfate group and a carboxylate group).

In some embodiments of any one of the embodiments described herein, themonosaccharide residues comprise no more than one charged group, thatis, 0 or 1 charged group.

In some embodiments of any one of the embodiments described herein, thepolysaccharide is characterized by a net charge (i.e., the differencebetween the number of anionic groups and the number of cationic groups)of from 0.2 to 1 electric charges per monosaccharide residue. In someembodiments, the net charge is from 0.2 to 0.9 electric charges permonosaccharide residue. In some embodiments, the net charge is from 0.3to 0.7 electric charges per monosaccharide residue. In some embodiments,the net charge is from 0.4 to 0.6 electric charges per monosaccharideresidue. In some embodiments, the net charge is about 0.5 electriccharges per monosaccharide residue.

In some embodiments of any one of the embodiments described herein, thewater-soluble polymer comprises one or more biopolymers.

Herein, the term “biopolymer” refers to a polymer naturally occurring ina living organism. Examples of biopolymers include, without limitation,polynucleotides (e.g., RNA and DNA), polypeptides, polysaccharides andconjugates thereof (e.g., glycoproteins and proteoglycans comprisingpolypeptide and polysaccharide moieties). It is to be appreciated thatbiopolymers may optionally comprise many different species of relatedmonomeric units (e.g., about 20 different types of amino acid residuesand/or various types of monosaccharide moieties) with little or norepetition of the specific species of monomeric units, yet areconsidered polymers because at least some of the monomeric units arerelated in structure (e.g., being amino acid residues or monosaccharidemoieties).

In some embodiments of any one of the embodiments described herein, thebiopolymer(s) comprises a polypeptide (optionally attached to one ormore saccharide moieties) and/or a polysaccharide.

Examples of suitable biopolymers comprising a polypeptide include,without limitation, mucins and lubricin.

Herein, the term “lubricin” refers to a proteoglycan (also known in theart as “proteoglycan 4”) of about 345 kDa. Human lubricin is encoded bythe PRG4 gene. The lubricin optionally comprises a polypeptide sequenceof isoform A and/or isoform B of lubricin, e.g., according to NCBIreference sequence NP_001121180.

Herein, the term “mucin” refers to a family of high molecular weightglycosylated proteins produced by many animals, and encompasses humanmucins such as, for example, mucin 1 (e.g., according to NCBI referencesequence NP_001018016), mucin 2 (e.g., according to NCBI referencesequence NP_002448), mucin 3A (e.g., according to NCBI referencesequence NP_005951), mucin 3B, mucin 4 (e.g., according to NCBIreference sequence NP_004523), mucin SAC, mucin 5B (e.g., according toNCBI reference sequence NP_002449), mucin 6 (e.g., according to NCBIreference sequence NP_005952), mucin 7 (e.g., according to NCBIreference sequence NP_001138478), mucin 8, mucin 12, mucin 13, mucin 15,mucin 16 (e.g., according to NCBI reference sequence NP_078966), mucin17 (e.g., according to NCBI reference sequence NP_001035194), mucin 19,and mucin 20 (e.g., according to NCBI reference sequence NP_001269435).

The polysaccharide may be a non-ionic polymer (as defined herein) or anionic polymer (as defined herein), e.g., according to any of theembodiments described herein relating to an ionic polysaccharide.

Hyaluronic acid (e.g., according to any of the respective embodimentsdescribed herein) is a non-limiting example of a suitable polysaccharideas well as a non-limiting example of a suitable anionic polymer.

In some embodiments of any one of the embodiments described herein, thewater-soluble polymer(s) is selected to enhance an affinity of theliposomes to the surface of a contact lens (according to any of therespective embodiments described herein), that is, the liposome lipidshave a greater affinity to the surface coated by the water-solublepolymer(s) than to the surface in the absence of the water-solublepolymer(s).

In some embodiments of any one of the embodiments described herein, thewater-soluble polymer(s) comprises an ionic polymer selected such thatthe liposomes are characterized by a surface charge having a signopposite a sign of a net charge of the ionic polymer.

In some embodiments of any one of the embodiments described herein, theliposomes are characterized by a negative surface charge (e.g., asdescribed herein in any one of the respective embodiments) and thewater-soluble polymer(s) comprises an ionic polymer having a netpositive charge (e.g., as described herein in any one of the respectiveembodiments). In some embodiments, the ionic polymer is a polysaccharidehaving a net positive charge (e.g., a cationic polysaccharide describedherein in any one of the respective embodiments).

In some embodiments of any one of the embodiments described herein, theliposomes are characterized by a positive surface charge (e.g., asdescribed herein in any one of the respective embodiments) and thewater-soluble polymer(s) comprises an ionic polymer having a netnegative charge (e.g., as described herein in any one of the respectiveembodiments). In some embodiments, the ionic polymer is a polysaccharidehaving a net negative charge (e.g., an anionic polysaccharide describedherein in any one of the respective embodiments). In some embodiments,the ionic polymer is hyaluronic acid (optionally hyaluronate salts, inaccordance with the definition of “hyaluronic acid” used herein).

In some embodiments of any one of the embodiments described herein, theamphiphilic lipid comprises at least one phospholipid which comprises aphosphoethanolamine group or N-alkyl derivative thereof (e.g., in anyone of the respective embodiments) and the water-soluble polymer(s)comprises an ionic polymer having a net negative charge (e.g., asdescribed herein in any one of the respective embodiments). In someembodiments, the ionic polymer is a polysaccharide having a net negativecharge (e.g., an anionic polysaccharide described herein). In someembodiments, the ionic polymer is hyaluronic acid.

Herein throughout, the term “at least one” means that the formulation orsolution comprises one water-soluble polymer or a mixture of two or morewater-soluble polymers.

In some embodiments of any of the embodiments described herein, theformulation or solution comprises one water-soluble polymer.

In some embodiments of any of the embodiments described herein, thewater-soluble polymers described herein comprise at least twowater-soluble polymers according to any of the respective embodimentsdescribed herein. In some embodiments, the water-soluble polymerscomprise at least three water-soluble polymers according to any of therespective embodiments described herein.

In some embodiments of any of the embodiments described herein, thewater-soluble polymers described herein comprise at least one biopolymer(according to any of the respective embodiments described herein) incombination with at least one non-ionic polymer (according to any of therespective embodiments described herein). In some embodiments, thewater-soluble polymers described herein comprise at least one mucinand/or lubricin biopolymer (according to any of the respectiveembodiments described herein) in combination with at least one non-ionicpolymer (according to any of the respective embodiments describedherein).

In some embodiments of any of the embodiments described herein, thewater-soluble polymers described herein comprise at least one biopolymer(according to any of the respective embodiments described herein) incombination with at least one ionic polymer (according to any of therespective embodiments described herein). In some embodiments, thewater-soluble polymers described herein comprise at least one mucinand/or lubricin biopolymer (according to any of the respectiveembodiments described herein) in combination with at least one ionicpolymer (according to any of the respective embodiments describedherein).

In some embodiments of any of the embodiments described herein, thewater-soluble polymers described herein comprise at least one ionicpolymer (according to any of the respective embodiments describedherein) in combination with at least one non-ionic polymer (according toany of the respective embodiments described herein).

In some embodiments of any one of the embodiments described herein, amolecular weight (i.e., average molecular weight or Mw, as known in theart) of the water-soluble polymer(s) is in a range of from 3 kDa to 10MDa. In some embodiments, the molecular weight is from 10 kDa to 10 MDa.In some embodiments, the molecular weight is from 20 kDa to 5 MDa. Insome embodiments, the molecular weight Mw is from 30 kDa to 2.5 MDa.

In some embodiments of any one of the embodiments described herein, amolecular weight (i.e., average molecular weight or Mw) of thewater-soluble polymer(s) is in a range of from 10 kDa to 1 MDa. In someembodiments, the molecular weight Mw is from 20 kDa to 500 kDa. In someembodiments, the molecular weight Mw is from 30 kDa to 250 kDa. In someembodiments, the water-soluble polymer(s) comprises a non-ionic polymer(according to any of the respective embodiments described herein) havingan aforementioned molecular weight. In some embodiments, the non-ionicpolymer is PVP and/or PEO having an aforementioned molecular weight.

In some embodiments of any one of the embodiments described herein, amolecular weight (i.e., average molecular weight or Mw) of thewater-soluble polymer(s) is in a range of from 0.05 to 10 MDa. In someembodiments, the molecular weight Mw is from 0.05 to 5 MDa. In someembodiments, the molecular weight Mw is from 0.5 to 10 MDa. In someembodiments, the molecular weight Mw is from 0.5 to 5 MDa. In someembodiments, the water-soluble polymer(s) comprises an ionic polymer(according to any of the respective embodiments described herein),optionally an ionic polysaccharide, having an aforementioned molecularweight. In some embodiments, the ionic polymer is hyaluronic acid havingan aforementioned molecular weight.

In some embodiments, a concentration of a water-soluble polymer in thesolution (according to any of the respective embodiments describedherein) is in a range of from 0.01 to 10 mg/ml. In some embodiments, theconcentration is in a range of from 0.03 to 10 mg/ml. In someembodiments, the concentration is in a range of from 0.1 to 10 mg/ml. Insome embodiments, the concentration is in a range of from 0.3 to 10mg/ml. In some embodiments, the water-soluble polymer is PVP, PEO and/oran ionic polymer and/or polysaccharide (e.g., as described herein in anyone of the respective embodiments), optionally hyaluronic acid.

In some embodiments, a concentration of each water-soluble polymer inthe solution (according to any of the respective embodiments describedherein) is in a range of from 0.01 to 10 mg/ml. In some embodiments, theconcentration is in a range of from 0.03 to 10 mg/ml. In someembodiments, the concentration is in a range of from 0.1 to 10 mg/ml. Insome embodiments, the concentration is in a range of from 0.3 to 10mg/ml. In some embodiments, the water-soluble polymer is PVP, PEO and/orhyaluronic acid.

In some embodiments, a total concentration of water-soluble polymer(s)in the solution (according to any of the respective embodimentsdescribed herein) is in a range of from 0.01 to 20 mg/ml. In someembodiments, the total concentration is in a range of from 0.03 to 20mg/ml. In some embodiments, the total concentration is in a range offrom 0.1 to 10 mg/ml. In some embodiments, the total concentration is ina range of from 0.3 to 10 mg/ml.

In some embodiments, a concentration of a water-soluble polymer in thesolution (according to any of the respective embodiments describedherein) is in a range of from 0.01 to 1 mg/ml. In some embodiments, theconcentration is in a range of from 0.03 to 1 mg/ml. In someembodiments, the concentration is in a range of from 0.1 to 1 mg/ml. Insome embodiments, the concentration is in a range of from 0.3 to 1mg/ml. In some embodiments, the water-soluble polymer is PVP, PEO and/oran ionic polymer and/or polysaccharide (e.g., as described herein in anyone of the respective embodiments), optionally hyaluronic acid.

In some embodiments, a concentration of each water-soluble polymer inthe solution (according to any of the respective embodiments describedherein) is in a range of from 0.01 to 1 mg/ml. In some embodiments, theconcentration is in a range of from 0.03 to 1 mg/ml. In someembodiments, the concentration is in a range of from 0.1 to 1 mg/ml. Insome embodiments, the concentration is in a range of from 0.3 to 1mg/ml. In some embodiments, the water-soluble polymer is PVP, PEO and/orhyaluronic acid.

In some embodiments, a total concentration of water-soluble polymer(s)in the solution (according to any of the respective embodimentsdescribed herein) is in a range of from 0.01 to 2 mg/ml. In someembodiments, the total concentration is in a range of from 0.03 to 2mg/ml. In some embodiments, the total concentration is in a range offrom 0.1 to 1 mg/ml. In some embodiments, the total concentration is ina range of from 0.3 to 1 mg/ml.

In some embodiments, a concentration of a water-soluble polymer in thesolution (according to any of the respective embodiments describedherein) is in a range of from 0.01 to 3 mg/ml. In some embodiments, theconcentration is in a range of from 0.01 to 1 mg/ml. In someembodiments, the concentration is in a range of from 0.01 to 0.3 mg/ml.In some embodiments, the concentration is in a range of from 0.01 to 0.1mg/ml. In some embodiments, the water-soluble polymer is PVP, PEO and/orhyaluronic acid.

In some embodiments, a concentration of each water-soluble polymer inthe solution (according to any of the respective embodiments describedherein) is in a range of from 0.01 to 3 mg/ml. In some embodiments, theconcentration is in a range of from 0.01 to 1 mg/ml. In someembodiments, the concentration is in a range of from 0.01 to 0.3 mg/ml.In some embodiments, the concentration is in a range of from 0.01 to 0.1mg/ml. In some embodiments, the water-soluble polymer is PVP, PEO and/orhyaluronic acid.

In some embodiments, a total concentration of water-soluble polymer(s)in the solution (according to any of the respective embodimentsdescribed herein) is in a range of from 0.01 to 6 mg/ml. In someembodiments, the total concentration is in a range of from 0.01 to 2mg/ml. In some embodiments, the total concentration is in a range offrom 0.01 to 0.6 mg/ml. In some embodiments, the total concentration isin a range of from 0.01 to 0.2 mg/ml.

In some embodiments of any one of the embodiments described herein, thewater soluble polymer(s) comprises hyaluronic acid, PVP and/or PEO at aconcentration of less than 3 mg/ml. In some embodiments, the hyaluronicacid, PVP and/or PEO concentration is at least 0.01 mg/ml. In someembodiments, the hyaluronic acid, PVP and/or PEO concentration is atleast 0.03 mg/ml. In some embodiments, the hyaluronic acid, PVP and/orPEO concentration is at least 0.1 mg/ml. In some embodiments, thehyaluronic acid, PVP and/or PEO is at least 0.3 mg/ml.

In some embodiments of any one of the embodiments described herein, thewater soluble polymer(s) comprises hyaluronic acid, PVP and/or PEO at aconcentration of less than 0.75 mg/ml. In some embodiments, thehyaluronic acid, PVP and/or PEO concentration is at least 0.01 mg/ml. Insome embodiments, the hyaluronic acid, PVP and/or PEO concentration isat least 0.03 mg/ml. In some embodiments, the hyaluronic acid, PVPand/or PEO concentration is at least 0.1 mg/ml. In some embodiments, thehyaluronic acid, PVP and/or PEO concentration is at least 0.3 mg/ml.

In some embodiments of any one of the embodiments described herein, thewater soluble polymer(s) comprises hyaluronic acid, PVP and/or PEO at aconcentration of less than 0.5 mg/ml. In some embodiments, thehyaluronic acid, PVP and/or PEO concentration is at least 0.01 mg/ml. Insome embodiments, the hyaluronic acid, PVP and/or PEO concentration isat least 0.03 mg/ml. In some embodiments, the hyaluronic acid, PVPand/or PEO concentration is at least 0.1 mg/ml. In some embodiments, thehyaluronic acid, PVP and/or PEO concentration is at least 0.3 mg/ml.

In some embodiments of any one of the embodiments described herein, thewater soluble polymer(s) comprises hyaluronic acid, PVP and/or PEO at aconcentration of less than 0.25 mg/ml. In some embodiments, thehyaluronic acid, PVP and/or PEO acid concentration is at least 0.01mg/ml. In some embodiments, the hyaluronic acid, PVP and/or PEOconcentration is at least 0.03 mg/ml. In some embodiments, thehyaluronic acid, PVP and/or PEO concentration is at least 0.1 mg/ml.

In some embodiments of any one of the embodiments described herein, thewater soluble polymer(s) comprises hyaluronic acid, PVP and/or PEO at aconcentration of less than 0.1 mg/ml. In some embodiments, thehyaluronic acid, PVP and/or PEO concentration is at least 0.01 mg/ml. Insome embodiments, the hyaluronic acid, PVP and/or PEO concentration isat least 0.03 mg/ml.

In some embodiments of any one of the embodiments described herein, aviscosity of the solution (which may reflect at least in part aconcentration of water-soluble polymer(s) therein) is no more than 1000cP (centipoise). In some embodiments, the viscosity is no more than 500cP. In some embodiments, the viscosity is no more than 200 cP. In someembodiments, the viscosity is no more than 100 cP. In some embodiments,the viscosity is no more than 50 cP. In some embodiments, the viscosityis no more than 20 cP. In some embodiments, the viscosity is no morethan 10 cP. In some embodiments, the viscosity is no more than 5 cP. Insome embodiments, the viscosity is no more than 3 cP. In someembodiments, the viscosity is no more than 2 cP. In some embodiments,the solution is an aqueous solution having a viscosity described herein.

Herein, viscosities of a solution are determined at a temperature of 20°C. and at a shear rate of 1 second⁻¹ (unless indicated otherwise).

Contact Lens:

In some of any one of the embodiments described herein which relate to acontact lens, according to any one of the aspects described herein, thecontact lens comprises a hydrogel surface. In some embodiments, thecontact lens comprises a hydrogel surface and a rigid center. In someembodiments, the contact lens consists essentially of a hydrogel.

The hydrogel may comprise any material known in the art for use incontact lens hydrogels. Examples of such hydrogel materials include,without limitation, alphafilcon A, asmofilcon A, balafilcon A, bufilconA, comfilcon A, crofilcon, deltafilcon A, dimefilcon, droxifilcon A,enfilcon A, etafilcon A, galyfilcon A, hefilcon A, hefilcon B,hilafilcon A, hilafilcon B, hioxifilcon A, hioxifilcon D, isofilcon,lidofilcon A, lidofilcon B, lotrafilcon B, mafilcon, methafilcon A,methafilcon B, narafilcon A, narafilcon B, ocufilcon A, ocufilcon B,ofilcon A, omafilcon A, perfilcon, phemfilcon A, polymacon, scafilcon A,senofilcon A, surfilcon, tefilcon, tetrafilcon A, tetrafilcon B,vifilcon A, and xylofilcon A.

In some embodiments of any one of the embodiments described herein, thehydrogel comprises a polymer selected from the group consisting ofpoly(2-hydroxyethyl methacrylate) and a silicone. In some embodiments,the polymer comprises a silicone. Such polymers may optionally comprisesmall amounts of additional monomers (e.g., cross-linking monomers)copolymerized with the 2-hydroxyethyl methacrylate or silicone monomer.For example, 2-hydroxyethyl methacrylate may optionally be copolymerizedwith vinyl pyrrolidone, methyl methacrylate, methacrylic acid (ananionic monomer), ethylene glycol dimethacrylate (a cross-linkingmonomer) and/or 3-(ethyldimethyl-ammonium)propyl methacrylamide (acationic monomer) in a contact lens hydrogel.

In some embodiments of any one of the embodiments described herein, thecontact lens surface material (e.g., polymer) is not capable ofselective binding to the water-soluble polymer(s) according to any ofthe respective embodiments described herein (e.g., hyaluronic acid, PVPand/or PEO).

In some embodiments of any one of the embodiments described herein, thewater-soluble polymer(s) according to any of the respective embodimentsdescribed herein (e.g., hyaluronic acid, PVP and/or PEO) binds to thecontact lens surface by non-specific adsorption.

In some embodiments of any one of the embodiments described herein, thecontact lens surface material (e.g., polymer) is capable of selectivebinding to the water-soluble polymer(s) according to any of therespective embodiments described herein. In some such embodiments, thewater-soluble polymer(s) comprises an ionic polymer according to any ofthe respective embodiments described herein (e.g., hyaluronic acid). Insome embodiments, the contact lens surface is a modified surface,selected to be capable of selective binding to the water-solublepolymer(s) (e.g., hyaluronic acid).

In some embodiments of any one of the embodiments described herein, thecontact lens surface is not modified in a manner which enhancesattachability of the water-soluble polymer(s) to the surface.

In some embodiments of any one of the embodiments described herein, thewater-soluble polymer(s) (e.g., non-modified hyaluronic acid, PVP and/orPEO) is not modified in a manner which enhances attachability of thewater-soluble polymer(s) to the surface.

In some embodiments of any one of the embodiments described herein, thehydrogel consists essentially of a polymer and an aqueous liquid(optionally water).

In some embodiments of any one of the embodiments described herein, thehydrogel in the contact lens comprises a polymer having no more than 2charged groups per kDa of polymer. In some embodiments, the polymer hasno more than 1 charged group per kDa. In some embodiments, the polymerhas no more than 0.5 charged group per kDa. In some embodiments, thepolymer has no more than 0.2 charged group per kDa. In some embodiments,the polymer has no more than 0.1 charged group per kDa.

In some embodiments of any one of the embodiments described herein, thehydrogel in the contact lens comprises a polymer having no more than 2negatively charged groups per kDa of polymer. In some embodiments, thepolymer has no more than 1 negatively charged group per kDa. In someembodiments, the polymer has no more than 0.5 negatively charged groupper kDa. In some embodiments, the polymer has no more than 0.2negatively charged group per kDa. In some embodiments, the polymer hasno more than 0.1 negatively charged group per kDa.

In some embodiments of any one of the embodiments described herein, thehydrogel in the contact lens comprises a polymer having a net charge ofno more than 2 electric charges per kDa of polymer. In some embodiments,the polymer has a net charge of no more than 1 charge per kDa. In someembodiments, the polymer has a net charge of no more than 0.5 charge perkDa. In some embodiments, the polymer has a net charge of no more than0.2 charge per kDa. In some embodiments, the polymer has a net charge ofno more than 0.1 charge per kDa. In some embodiments, the net charge isa negative net charge.

Without being bound by any particular theory, it is believed that arelatively low level of charged groups and/or net charge may beadvantageous when the polymer of the hydrogel has a net charge havingthe same sign as a net charge of a water-soluble polymer(s) whichcomprises an ionic polymer (according to any of the respectiveembodiments described herein), in order to minimize electrostaticrepulsion between the ionic polymer described herein and the hydrogel.

In some embodiments of any one of the embodiments described herein, thecontact lens comprises a surface which is positively charged orneutrally charged, that is, the net charge is not a negative net charge.In some such embodiments, the liposomes are characterized by a positivesurface charge (e.g., liposomes comprising phosphatidylcholine, asdescribed herein in any one of the respective embodiments). In suchembodiments, there is typically no significant electrostatic attractionbetween the liposomes and the contact lens surface, and thus thewater-soluble polymer(s) described herein may be particularly useful formediating adherence of the liposome lipids to the lens surface.

In some embodiments of any one of the embodiments described herein, thecontact lens comprises a surface which is negatively charged orneutrally charged, that is, the net charge is not a positive net charge.In some such embodiments, the liposomes are characterized by a negativesurface charge. In such embodiments, there is typically no significantelectrostatic attraction between the liposomes and the contact lenssurface, and thus the water-soluble polymer(s) described herein may beparticularly useful for mediating adherence of the liposome lipids tothe lens surface.

Carrier and Formulation:

In some embodiments of any one of the embodiments described herein, thecarrier is an ophthalmically acceptable carrier. In some suchembodiments, the solution can be allowed to remain on the contact lensfollowing rinsing and/or immersing in the solution, as the residualsolution will not harm the eye when the contact lens is placed on theeye.

Herein, the phrase “ophthalmically acceptable carrier” refers to acarrier or a diluent that does not cause significant irritation to asubject when contacted with an eye (e.g., cornea and/or sclera) of thesubject, and does not abrogate the activity and properties of thewater-soluble polymer(s) and liposomes in the solution (e.g., theirability to reduce a friction coefficient of a contact lens surface).

In some embodiments of any one of the embodiments described herein, thecarrier is not an ophthalmically acceptable carrier. Examples of suchcarriers include, without limitation, carriers comprising a preservativeand/or a concentration of preservative which is not ophthalmicallyacceptable. Such carriers may be suitable, for example, for immersing acontact lens for an extended period of time, and/or for storage for anextended period of time, while limiting the risk of bacterial growth inthe solution. Typically, a solution comprising such a carrier is rinsedwith an ophthalmically acceptable liquid (e.g., water, saline) solutionprior to placing the contact lens on the eye.

In some embodiments of any one of the embodiments described herein, thesolution is formulated as a solution suitable for storage of contactlenses (e.g., soft contact lenses), for example, as known in the art.Examples of ingredients suitable for such solutions, which may beoptionally included in the solution according to some embodiments of theinvention, include, without limitation, buffers (e.g., borate and/orphosphate, having a pH of from about 6.5 to 7.6), wettability enhancersand humectants (optionally additional water-soluble polymers such aspolyvinyl alcohol and/or hydroxypropylmethylcellulose).

Techniques for formulation and administration of compounds may be foundin “Remington's Pharmaceutical Sciences” Mack Publishing Co., Easton,Pa., latest edition, which is incorporated herein by reference.

Solutions according to any one of the embodiments of the presentinvention may be manufactured by processes well known in the art, e.g.,by means of conventional mixing or dissolving processes.

Solutions for use in accordance with the present invention thus may beformulated in conventional manner using one or more ophthalmicallyacceptable carriers, which facilitate processing of the water-solublepolymer(s) and/or liposomes into preparations which can be used asdescribed herein. The water-soluble polymer(s) and/or liposomesdescribed herein may be formulated as an aqueous solution per se.Additionally, the solution may be in the form of a suspension and/oremulsions (e.g., the aqueous phase of a suspension or water-in-oil,oil-in-water or water-in-oil-in-oil emulsion), for example, in order toincrease the viscosity of the formulation.

In some embodiments, the water-soluble polymer(s) and/or liposomesdescribed herein may be in powder form for constitution with a suitablevehicle such as water, e.g., sterile, pyrogen-free water, before use.

The solutions may be formulated wherein the active ingredient(s)(water-soluble polymer(s) and/or liposomes) are contained in an amounteffective to achieve the intended purpose, for example, an amounteffective to prevent, alleviate or ameliorate symptoms of a disorder inthe subject being treated.

The amount of a composition to be administered will, of course, bedependent on the subject being treated, the severity of the affliction,the manner of administration, the judgment of the prescribing physician,etc.

Kits and Articles:

According to another aspect of embodiments of the invention, there isprovided a kit comprising at least one contact lens; and a solution foruse in rinsing and/or immersing therein a contact lens and/or for use intreatment of ocular discomfort, according to any one of the embodimentsdescribed herein.

Typically, the kit will comprise at least two contact lenses, e.g., atleast one pair of contact lenses.

In some embodiments of any one of the embodiments described herein, thekit comprises at least 6 contact lenses. In some embodiments, the kitcomprises at least 10 contact lenses. In some embodiments, the kitcomprises at least 20 contact lenses. In some embodiments, the kitcomprises at least 30 contact lenses. In some embodiments, the kitcomprises at least 50 contact lenses. In some embodiments, the kitcomprises at least 100 contact lenses.

In some embodiments of any one of the embodiments described herein, thekit comprises a plurality of packaging units (e.g., blister packs), eachpackaging unit comprising one contact lens.

In some embodiments of any one of the embodiments described herein, thekit comprises a plurality of packaging units (e.g., blister packs), eachpackaging unit comprising one pair of contact lenses.

In some embodiments of any one of the embodiments described herein, acontact lens in the kit is immersed in a solution. In some embodiments,the contact lens is a soft contact lens, and the solution is a solutionsuitable for storage of soft contact lenses, for example, as known inthe art. The solution may optionally be the solution according to someembodiments of the invention, or a different solution, for example, astandard solution for storage of contact lenses.

In some embodiments of any one of the embodiments described herein, theat least one contact lens in the kit is immersed in the solutioncomprising liposomes and water-soluble polymer, as described herein inany one of the respective embodiments, for example, packaged in apackaging unit (e.g., blister pack) containing the solution.

Without being bound by any particular theory, it is believed thatpackaging a contact lens immersed in the solution comprising liposomesand water-soluble polymer provides ample time for the water-solublepolymer(s) and liposome lipids to coat the contact lens surface, asdescribed herein in any one of the respective embodiments, and avoidsthe need for a user of the kit to contact the contact lens with thesolution.

In some embodiments of any one of the embodiments described herein, thesolution is formulated as a solution suitable for storage of contactlenses (e.g., soft contact lenses), according to any of the respectiveembodiments described herein.

In some embodiments of any one of the embodiments described herein, theat least one contact lens and the solution comprising liposomes andwater-soluble polymer(s), as described herein in any one of therespective embodiments, are packaged separately within the kit. In suchembodiments, the at least one contact lens may optionally be immersed ina solution other than the solution comprising liposomes andwater-soluble polymer(s), or not be immersed in any solution. In someembodiments, the solution comprising liposomes and water-solublepolymer(s), as described herein in any one of the respectiveembodiments, is packaged in a container configured for dispensing thesolution, optionally configured for dispensing a predetermined volume ofthe solution. In some embodiments, the kit includes instructions forrinsing a contact lens with the solution and/or immersing a contact lensin the solution (e.g., for a predetermined period of time) prior towearing the contact lens, to thereby reduce the friction coefficient ofthe contact lens surface prior to wearing.

According to another aspect of embodiments of the invention, there isprovided an article-of-manufacturing comprising the solution describedherein for use in rinsing and/or immersing therein a contact lens,and/or for use in treatment of ocular discomfort. According to thisaspect, the solution is packaged in a container configured fordispensing the solution. Examples of such containers include, withoutlimitation, squeezable containers configured for dispensing the solutionupon squeezing the container, spray containers configures for dispensingthe solution as an aerosol and/or a liquid jet, containers configuredfor dispensing the solution slowly (e.g., as discrete drops), andmetered-dose containers configured for dispensing a predetermined amountof solution.

In some embodiments, the container is configured for dispensing apredetermined volume of the solution (e.g., a predetermined volume in arange of from 0.5 to 20 ml, optionally from 1 to 10 ml).

Solutions (or formulations) according to embodiments of the presentinvention may, if desired, be presented in a pack or dispenser device(e.g., as described herein), such as an FDA (the U.S. Food and DrugAdministration) approved kit, which may contain one or more unit dosageforms containing the active ingredient(s) (e.g., water-solublepolymer(s) and/or liposomes described herein). The pack may, forexample, comprise metal or plastic foil, such as, but not limited to ablister pack. The pack or dispenser device may be accompanied byinstructions for administration. The pack or dispenser may also beaccompanied by a notice associated with the container in a formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the compositions for human or veterinaryadministration. Such notice, for example, may be of labeling approved bythe U.S. Food and Drug Administration for prescription drugs or of anapproved product insert. Solutions comprising water soluble polymer(s)and/or liposomes, as described herein in any one of the respectiveembodiments, formulated in an ophthalmically acceptable carrier may alsobe prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition or diagnosis, as is detailed herein.

Additional Definitions

Herein, the term “alkyl” describes a saturated or unsaturated aliphatichydrocarbon including straight chain and branched chain groups.Preferably, the alkyl group has 1 to 20 carbon atoms. Whenever anumerical range; e.g., “1 to 20”, is stated herein, it implies that thegroup, in this case the alkyl group, may contain 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. Morepreferably, the alkyl is a medium size alkyl having 1 to 10 carbonatoms. Most preferably, unless otherwise indicated, the alkyl is a loweralkyl having 1 to 4 carbon atoms. The alkyl group may be substituted ornon-substituted. Substituted alkyl may have one or more substituents,whereby each substituent group can independently be, for example,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine,halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy,thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide,carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.

When unsaturated, an alkyl may comprise at least one carbon-carbondouble bond, in which case it may also be referred to as an “alkenyl”,and/or at least one carbon-carbon triple bond, in which case it may alsobe referred to as an “alkynyl”.

The alkyl group can be an end group, as this phrase is defined herein,wherein it is attached to a single adjacent atom, or a linking group, asthis phrase is defined herein, which connects two or more moieties.

Herein, the phrase “end group” describes a group (e.g., a substituent)that is attached to a single moiety in the compound via one atomthereof.

The phrase “linking group” describes a group (e.g., a substituent) thatis attached to two or more moieties in the compound.

The term “cycloalkyl” describes an all-carbon monocyclic or fused ring(i.e., rings which share an adjacent pair of carbon atoms) group whereone or more of the rings does not have a completely conjugatedpi-electron system. The cycloalkyl group may be substituted ornon-substituted. Substituted cycloalkyl may have one or moresubstituents, whereby each substituent group can independently be, forexample, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, amine,halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy,thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide,carboxy, thiocarbamate, urea, thiourea, carbamate, amide, and hydrazine.The cycloalkyl group can be an end group, as this phrase is definedherein, wherein it is attached to a single adjacent atom, or a linkinggroup, as this phrase is defined herein, connecting two or moremoieties.

The term “aryl” describes an all-carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. The aryl groupmay be substituted or non-substituted. Substituted aryl may have one ormore substituents, whereby each substituent group can independently be,for example, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic,amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy,aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo,sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide,and hydrazine. The aryl group can be an end group, as this term isdefined herein, wherein it is attached to a single adjacent atom, or alinking group, as this term is defined herein, connecting two or moremoieties.

The term “heteroaryl” describes a monocyclic or fused ring (i.e., ringswhich share an adjacent pair of atoms) group having in the ring(s) oneor more atoms, such as, for example, nitrogen, oxygen and sulfur and, inaddition, having a completely conjugated pi-electron system. Examples,without limitation, of heteroaryl groups include pyrrole, furan,thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine,quinoline, isoquinoline and purine. The heteroaryl group may besubstituted or non-substituted. Substituted heteroaryl may have one ormore substituents, whereby each substituent group can independently be,for example, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic,amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy,aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo,sulfonamide, carboxy, thiocarbamate, urea, thiourea, carbamate, amide,and hydrazine. The heteroaryl group can be an end group, as this phraseis defined herein, where it is attached to a single adjacent atom, or alinking group, as this phrase is defined herein, connecting two or moremoieties. Representative examples are pyridine, pyrrole, oxazole,indole, purine and the like.

The term “heteroalicyclic” describes a monocyclic or fused ring grouphaving in the ring(s) one or more atoms such as nitrogen, oxygen andsulfur. The rings may also have one or more double bonds. However, therings do not have a completely conjugated pi-electron system. Theheteroalicyclic may be substituted or non-substituted. Substitutedheteroalicyclic may have one or more substituents, whereby eachsubstituent group can independently be, for example, alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide,phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy,thioaryloxy, cyano, nitro, azo, sulfonamide, carboxy, thiocarbamate,urea, thiourea, carbamate, amide, and hydrazine. The heteroalicyclicgroup can be an end group, as this phrase is defined herein, where it isattached to a single adjacent atom, or a linking group, as this phraseis defined herein, connecting two or more moieties. Representativeexamples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran,morpholine and the like.

As used herein, the terms “amine” and “amino” describe both a —NRxRygroup —NRx- group, wherein Rx and Ry are each independently hydrogen,alkyl, cycloalkyl, aryl, heteroaryl or heteroalicyclic, as these termsare defined herein. When Rx or Ry is heteroaryl or heteroalicyclic, theamine nitrogen atom is bound to a carbon atom of the heteroaryl orheteroalicyclic ring.

The amine group can therefore be a primary amine, where both Rx and Ryare hydrogen, a secondary amine, where Rx is hydrogen and Ry is alkyl,cycloalkyl, aryl, heteroaryl or heteroalicyclic, or a tertiary amine,where each of Rx and Ry is independently alkyl, cycloalkyl, aryl,heteroaryl or heteroalicyclic.

The terms “halide” and “halo” refer to fluorine, chlorine, bromine oriodine.

The term “haloalkyl” describes an alkyl group as defined herein, furthersubstituted by one or more halide(s).

The term “phosphonate” refers to an —P(═O)(ORx)-OR_(Y) end group, or toa —P(═O)(ORx)-O— linking group, where Rx and R_(Y) are as definedherein.

The term “sulfoxide” or “sulfinyl” describes a —S(═O)—Rx end group or—S(═O)— linking group, where Rx is as defined herein.

The terms “sulfonate” and “sulfonyl” describe a —S(═O)₂—Rx end group or—S(═O)₂— linking group, where Rx is as defined herein.

The term “sulfonamide”, as used herein, encompasses both S-sulfonamideand N-sulfonamide end groups, and a —S(═O)₂—NRx- linking group.

The term “S-sulfonamide” describes a —S(═O)₂—NRxR_(Y) end group, with Rxand R_(Y) as defined herein.

The term “N-sulfonamide” describes an RxS(═O)₂—NR_(Y)— end group, whereRx and R_(Y) are as defined herein.

The term “carbonyl” as used herein, describes a —C(═O)—Rx end group or—C(═O) linking group, with Rx as defined herein.

The term “acyl” as used herein, describes a —C(═O)—Rx end group, with Rxas defined herein.

The terms “hydroxy” and “hydroxyl” describe a —OH group.

The term “alkoxy” describes both an —O-alkyl and an —O-cycloalkyl endgroup or linking group, as defined herein.

The term “aryloxy” describes both an —O-aryl and an —O-heteroaryl endgroup or linking group, as defined herein.

The term “thiohydroxy” describes a —SH group.

The term “thioalkoxy” describes both a —S-alkyl end group or linkinggroup, and a —S-cycloalkyl end group or linking group, as definedherein.

The term “thioaryloxy” describes both a —S-aryl and a —S-heteroaryl endgroup or linking group, as defined herein.

The terms “cyano” and “nitrile” describe a —CN group.

The term “nitro” describes an —NO₂ group.

The term “azo” describes an —N═N-Rx end group or —N═N═ linking group,with Rx as defined herein.

The terms “carboxy” and “carboxyl”, as used herein, encompasses bothC-carboxy and O-carboxy end groups, and a —C(═O)—O— linking group.

The term “C-carboxy” describes a —C(═O)—ORx end group, where Rx is asdefined herein.

The term “O-carboxy” describes a —OC(═O)—Rx end group, where Rx is asdefined herein.

The term “urea” describes a —NRxC(═O)—NRyRw end group or —NRxC(═O)—NRy-linking group, where Rx and Ry are as defined herein and Rw is asdefined herein for Rx and Ry.

The term “thiourea” describes a —NRx-C(═S)—NRyRw end group or a—NRx-C(═S)—NRy- linking group, with Rx, Ry and Ry as defined herein.

The term “amide”, as used herein, encompasses both C-amide and N-amideend groups, and a —C(═O)—NRx- linking group.

The term “C-amide” describes a —C(═O)—NRxRy end group, where Rx and Ryare as defined herein.

The term “N-amide” describes a RxC(═O)—NRy- end group, where Rx and Ryare as defined herein.

The term “carbamyl” or “carbamate”, as used herein, encompassesN-carbamate and O-carbamate end groups, and a —OC(═O)—NRx- linkinggroup.

The term “N-carbamate” describes an RyOC(═O)—NRx- end group, with Rx andRy as defined herein.

The term “O-carbamate” describes an —OC(═O)—NRxRy end group, with Rx andRy as defined herein.

The term “thiocarbamyl” or “thiocarbamate”, as used herein, encompassesboth O-thiocarbamate, S-thiocarbamate and N-thiocarbamate end groups,and a —OC(═S)—NRx- or —SC(═O)—NRx- linking group.

The term “O-thiocarbamate” describes a —OC(═S)—NRxRy end group, with Rxand Ry as defined herein.

The term “S-thiocarbamate” describes a —SC(═O)—NRxRy end group, with Rxand Ry as defined herein.

The term “N-thiocarbamate” describes an RyOC(═S)NRx- or RySC(═O)NRx-endgroup, with Rx and Ry as defined herein.

The term “guanidine” describes a —RxNC(═N)—NRyRw end group or—RxNC(═N)—NRy- linking group, where Rx, Ry and Rw are as defined herein.

The term “hydrazine”, as used herein, describes a —NRx-NRyRw end groupor —NRx-NRy- linking group, with Rx, Ry, and Rw as defined herein.

As used herein the term “about” refers to ±10%, and optionally ±5%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find experimentalsupport in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention in anon-limiting fashion.

Materials and Methods

Materials:

Hyaluronic acid (sodium hyaluronate, 1 and 1.5 MDa) was obtained fromLifecore Biomedical.

Phosphate buffer saline (PBS) was obtained from Sigma-Aldrich.

Phosphatidylcholines (PC), including dimyristoylphospatidylcholine(1,2-dimyristoyl-sn-glycero-3-phosphocholine; DMPC) and hydrogenated soyPC (HSPC), were obtained from Lipoid GmbH.

Polyethylene glycol (PEG or PEO), 200 kDa molecular weight, was obtainedfrom Sigma-Aldrich.

Polyvinylpyrrolidone (PVP), 40 kDa molecular weight, was obtained fromSigma-Aldrich.

Etafilcon A (1-Day ACUVUE®) and Narafilcon A (1-Day TruEye®) contactlenses were obtained from Johnson & Johnson, immersed in saline solutionin a blister-pack. The composition, water content and modulus of thecontact lenses are as follows. Etafilcon A lenses contain2-hydroxyethylmethacrylate (HEMA) and methacrylic acid (MA), have awater content of 58%, and a modulus of 0.3 MPa. Narafilcon A lensescontain silicone, have a water content of 46%, and a modulus of 0.66MPa.

A saline commercial lens cleaning fluid (Sensitive Eyes® Plus salinesolution) was obtained from Bausch & Lomb, and is referred to herein as“B&L saline”.

Water used was purified by Barnsted NanoPure systems to a resistance of18.2 MΩ-cm resistance with total organic content levels of less thanapproximately 1 part per billion.

Liposome Preparation (Multilamellar Vesicles):

Multilamellar vesicles (MLV) composed either ofdimyristoylphosphatidylcholine(1,2-dimyristoyl-sn-glycero-3-phosphocholine; DMPC) or of hydrogenatedsoy PC (HSPC) were prepared by hydrating the lipids at a temperature atleast 5° C. above the lipid melting point (TM), followed by sonication,in phosphate buffer saline (PBS). Where MLV liposomes were mixed withhyaluronic acid (HA), the polymer solution (in PBS) was prepared inadvance, and after full dissolution of the HA, the solution was warmedto a temperature at least 5° C. above the lipid T_(M), and added to thelipids, followed by stirring to mix.

Liposome Preparation (Small Unilamellar Vesicles):

Multilamellar vesicles (MLV) composed of dimyristoylphosphatidylcholine(DMPC) or hydrogenated soy PC (HSPC) were prepared by hydrating thelipids at a temperature above the lipid melting point (T_(M)), accordingto the procedures described hereinabove. In order to obtain smallunilamellar vesicles (SUV), the MLVs were downsized by stepwiseextrusion through polycarbonate membranes, starting with a 400 nm andending with 50 nm pore size membrane, using a Lipex 100 mL extrudersystem (Northern Lipids, Vancouver, Canada), at a temperature above thelipid T_(M).

Where SUV liposomes were mixed with a polymer, the polymer solution (inPBS) was prepared in advance, and after full dissolution of the polymer,the polymer solution was added to the lipids, followed by stirring tomix for 2 hours.

Multilamellar vesicles and small unilamellar vesicles composed of otherpure phosphatidylcholines, such as dipalmitoylphosphatidylcholine(DPPC), dilauroylphosphatidylcholine (DLPC) and/ordistearoylphosphatidylcholine (DSPC), according to the proceduresdescribed hereinabove.

Friction Measurements:

Friction tests were performed with a UMT model tribometer (Bruker).Contact lenses were mounted on a cornea-mimicking holder, which has atypical geometry resembling the human cornea, as shown in FIGS. 1A and1B. The contact lens was then positioned opposite a glass plate andimmersed in B&L saline (Example 1) or PBS (Example 2) during themeasurement. The normal loads used were 3 grams, 5 grams, 10 grams and40 grams.

The friction coefficient was calculated by dividing the measured lateralforce during sliding by the applied normal force. Friction coefficientvalues are those of kinetic friction, which is related to the forces inthe system that are measured when there is a sliding motion of thecontact lens on the opposing glass surface. Parameters were as follows:sliding velocity 1 mm per second, frequency 1 Hz, and dwell time of 5seconds prior to initiation of motion. Experiments were conducted at atemperature of 36±0.5° C. (Example 1) or 37±1° C. (Example 2).

Each friction coefficient value (μ) is an average of frictionmeasurements for at least 5 different etafilcon A (HEMA/MA) lenses, orfor at least 3 different narafilcon A (silicone) lenses, for eachimmersion condition. Moreover, each friction measurement is an averageover 180 cycles for each of 2 to 3 different contact position on theglass surface. The same glass surface was used for one entire set ofexperiments for a given lens type, and the order of measurements was asfollows: first, saline controls; then a lens that had been immersed inHA; then a lens that had been immersed in HSPC; then a lens that hadbeen immersed in HSPC+HA; then a lens that had been immersed in DMPC;then a lens that had been immersed in DMPC+HA. Between each differentlens the B&L saline or PBS immersing the lens/substrate system wasreplaced by fresh B&L saline or PBS, respectively. The glass surface wasthen changed, and the measurements repeated (5 times for etafilcon A and3 times for narafilcon A).

In one case, following the full set of measurements with a given glasssubstrate, the measurement for the (HSPC+HA)-immersed lens on the samesubstrate was repeated, and the earlier measured value (for the same(HSPC+HA)-immersed lens) was reproduced.

The mean pressure P over the contact area A was determined according tothe equation: P=F_(N)/A, where FN is the applied normal load and, fromHertzian contact mechanics [Johnson, K. L., Contact Mechanics 2004,London: Cambridge University Press], A=π(RF_(N)/K)^(2/3), where R is theradius of the rigid cornea-mimicking holder and K is the Young's modulusof the contact lens.

Dynamic Light Scattering (DLS):

Dynamic light scattering (DLS) measurements of the various suspensionswere determined using a ZetaSizer μV apparatus (Malvern Instruments).

Example 1 Hyaluronic Acid Lubrication Solutions

Lenses were removed from their blister-pack, where they had beenimmersed in a saline solution, and were then immersed for 2 days ineither an HA solution in PBS, a liposome solution in PBS, or a combinedHA+liposome solution in PBS. Immersion was carried out in the originalblister-pack to which the immersing solution was added after removingthe original saline. For the control measurements where lenses were notimmersed in one of the solutions, the lenses were used immediatelyfollowing removal from their original blister pack.

Prior to measurements in the tribometer, in all samples (including thecontrols), the lenses were thoroughly rinsed by a stream of B&L saline.The lenses were then mounted on the tribometer holder and frictionforces measured while sliding against a glass surface and immersed inB&L saline.

The glass substrates used were thin 24 mm×24 mm coverglasses (KnittelGlaser, Germany). They were removed from their pack (edge-handled withlatex gloves throughout), and glued into a standard 35 mm diameterpolystyrene Petri dish using Devcon® 5 Minute® 2-component epoxy. Justprior to the friction measurements, the upper glass surface was wipedwith an ethanol-moistened Kimwipes® tissue, then rinsed in de-ionizedwater to remove any ethanol traces, and the Petri dish then filled withB&L saline.

Results:

Dynamic light scattering (DLS) measurements showed that HA in PBS had ahydrodynamic diameter of 135±20 nm. For the MLV HSPC and DMPC liposomesin PBS solution, DLS measurements yielded diameters of 3±1.5 μm and1.4±0.7 μm, respectively.

DLS measurements of the MLV's HSPC and DMPC liposomes mixtures with HAindicated diameters of 2.5±1.5 μm and 2.8±1.5 μm, respectively.

Friction coefficients were measured in B&L saline environment eitherfollowing removal of the lens from the blister-pack and rinsing in B&Lsaline (labeled ‘saline’ in the figure legends), or following immersionin PBS solutions containing the tested liposomes (at a concentration of45 mM) and/or HA (1 M; 0.2 mg/ml), and rinsing in B&L saline, for thetwo lens types.

The applied loads (L) were 5 grams, 10 grams or 40 grams, and thecorresponding mean pressures P (in Atm units) are presented in FIGS. 2and 3, respectively as L/P.

As shown in FIGS. 2 and 3, the sliding friction coefficients μ of lensesthat were only rinsed in B&L saline following removal from theirblister-pack, and then slided across a glass slide immersed in B&Lsaline, was in the range 0.08±0.04 for HEMA hydrogel lenses (EtafilconA) and 0.2±0.1 for Silicone hydrogel lenses (Narafilcon A). These valuesare considered as the baseline control relative to the values obtainedwith other solutions, and are designated herein as μ₀.

As further shown in FIGS. 2 and 3, following immersion in HA solution,the sliding friction coefficient μ decreased relative to the baselinevalue μ₀, by 30% and 50%, for the Etafilcon A and the Narafilcon Alenses, respectively.

Following immersion in liposome solutions, a significant reduction inthe sliding friction coefficient μ relative to μ₀ was generally noted,ranging between 25% to about 75% for the HSPC liposomes and between 65%to 92% for the DMPC liposomes.

Following immersion in the HA/liposome mixtures, substantially higherreduction in sliding friction coefficients μ relative to μ₀ wereinvariably observed, ranging from about 2-fold reduction for Etafilcon(HEMA) immersed in HA+HSPC to more-than-10-fold reduction for Narafilcon(silicone) immersed in HA+DMPC.

In some cases, the friction coefficients were somewhat lower at thehigher loads.

These results present a synergistic effect of a solution containing bothHA and liposomes. It is to be understood that in sliding frictioncoefficient, when two or more lubricants are measured alone and incombination, it is expected that the combination would result inaveraged values of the friction coefficient. However, surprisingly, asolution containing HA and the liposomes resulted in frictioncoefficient values which were substantially lower than the frictioncoefficient values obtained for either component alone, thusdemonstrating a synergistic effect.

It is noted that all measurements were performed following 2-dayimmersion of the lenses in the tested solutions and a subsequentthorough rinse in a stream of B&L saline, such that subsequentmeasurements were made in B&L saline alone. It is therefore assumed thatthere was no trace of free HA or liposomes in the liquid surrounding thelenses in the tribometer.

Some Non-Limiting Mechanistic Insights:

Without being bound by any particular theory, the following provides atentative explanation of the results presented above.

The reduction in the friction coefficient upon immersion in HA solutionand a subsequent rinse in B&L saline may be regarded as evidence of aninteraction and possible attachment of the HA to the surface of thehydrogel of the contact lens.

HA is known as an additive to eye-drops and to lens immersion solutionsdue to its therapeutic properties [Price et al. Journal of Plastic,Reconstructive & Aesthetic Surgery, 2007. 60(10): p. 1110-1119], and isknown not to be a good boundary lubricant [Seror et al.,Biomacromolecules, 13(11):3823-3832, (2012)]; Benz et al. Journal ofBiomedical Materials Research Part A, 2004. 71A:6-15], although viscoussolutions of HA, similarly to other viscous solutions, have beenconsidered to act as non-boundary lubricants [Doughty, Contact Lens andAnterior Eye 1999, 22:116-126].

The higher reduction (relative to saline and to HA solutions) in thefriction coefficient upon immersion in liposomes solution and asubsequent rinse in B&L saline may be regarded as evidence of coverageof the contact lens hydrogel surface. PC liposomes are well known to actas efficient boundary lubricants, hence the (generally observed)reduction in μ relative to μ₀.

It is assumed that the low pressures at which measurements wereperformed, which are lower relative to earlier studies of lubrication byliposomes, the DMPC lipids provide better lubrication than the HSPC,possibly because that at 36° C., the DMPC are in their liquid disordered(LD) phase (T_(M)(DMPC)=24° C.) and hence are more highly hydrated thanthe HSPC, which at 36° C. is in its solid ordered (SO) phase(T_(M)(HSPC)=53° C.). It is noted that in previous studies, at much highpressures, the situation is reversed, and HSPC liposomes are the betterlubricants since their bilayers are more robust than the DMPC ones[Goldberg, R., et al., Advanced Materials, 2011, 23:3517-3521; Sorkin,R., et al., Biomaterials, 2013. 34:5465-5475].

When the lenses are immersed in a mixture of the liposomes and HA, HAadsorbs on the lenses and, in this surface-attached form, complexes withthe lipids to form highly lubricating boundary layers.

These findings are also qualitatively consistent with the somewhatweaker effect that HA has either on its own or, synergistically, withthe liposomes, when Etafilcon lenses (HEMA+MA groups) are used relativeto Narafilcon (silicone).

The Etafilcon lens is slightly negatively charged due to the methacrylicacid (MA) groups, whereby the Narafilcon is uncharged. HA exhibits bothnegative charge and hydrophobicity. It is therefore assumed that whileHA may interact via hydrophobic and electrostatic interactions, itadheres more weakly to negatively-charged surfaces such as HEMA. Thislower absorbance of HA on the Etafilcon accounts for the weakerreduction in friction for Etafilcon vs. Narafilcon, both when HA aloneis used, and when it is used together with liposomes in the immersingsolutions, thus indicating a role for HA absorbance to the lens surfacein reducing friction coefficient and increasing lubricity.

Additional Measurements:

Friction coefficients are measured for contact lenses, according toprocedures such as described hereinabove, following immersion insolutions comprising different concentrations of liposomes (e.g., otherthan the abovementioned 45 mM), different concentrations of HA (e.g.,other than the abovementioned 0.2 mg/ml), different types of liposomes(e.g., small unilamellar vesicles) and/or different phospholipids in theliposomes (e.g., dipalmitoylphosphatidylcholine (DPPC),dilauroylphosphatidylcholine (DLPC) and/or distearoylphosphatidylcholine(DSPC)), in order to assess the effect of liposome and/or HAconcentration, phospholipid, and/or liposome type on the measuredfriction coefficient. The concentrations of HA (optionally non-modifiedHA) are optionally no more than about 1 mg/ml (e.g., within a range offrom 0.01 to 1 mg/ml), in order to maintain a liquid nature of thesolutions. The liposome concentrations are optionally characterized by aphospholipid concentration in a range of from 0.5 mM to 500 mM.

In addition, friction coefficients are measured for contact lenses,according to any of the procedures described hereinabove, except thatthe lenses are not rinsed after immersion.

In order to assess the activity of HA (optionally modified HA) andliposomes at the surface of contact lens hydrogels, the HA and/orliposomes are labeled (e.g., by a fluorescent label). Adsorption of HAand/or liposomes onto the surface of the hydrogel is measured bydetecting and optionally quantifying levels of labeled HA and/orliposomes at the hydrogel surface. In addition, the effect of HA onliposome adsorption and/or the effect of liposomes on HA adsorption areoptionally determined (e.g., quantitatively) by comparing adsorption inthe presence of liposomes and HA with adsorption of liposomes without HAand/or HA without liposomes.

HA (optionally modified HA) is optionally labeled by fluorescentlabeling (e.g. with fluorescein) or by other approaches, optionallybiotin-avidin chemistry, for example, using biotinylated HA (e.g., asdescribed below), and detecting the biotinylated HA by contacting asample with labeled (e.g., fluorescent-labeled) avidin.

Liposomes are optionally labeled by contact of the phospholipids with alipophilic marker (e.g., a fluorescent compound), such that the markeris incorporated into the liposome phospholipid layer; by covalentlycoupling the phospholipids with a lipophilic marker (e.g., a fluorescentcompound), optionally 7-nitro-2,1,3-benzoxadiazole (NBD), which may becoupled, for example, to amine groups in a phosphoethanolamine moietyand/or in an amine-substituted fatty acyl moiety; and/or by preparationof the liposomes in a solution of a marker (e.g., a fluorescentcompound), such that the marker is entrapped within the liposome.

The HA and liposomes are preferably labeled by readily distinguishablelabels (e.g., fluorescent labels with different emission and/orabsorption wavelengths), in order to facilitate measurements of each ofHA and liposomes in the present of a combination thereof.

Example 2 Additional Lubrication Solutions

Lenses were removed from their container, where they had been immersedin a phosphate buffer saline (PBS) solution, and were rinsed using PBS.The lenses were then immersed for 2 days in a PBS solution of liposomesand/or a polar polymer (hyaluronic acid (HA), polyvinylpyrrolidone (PVP)or polyethylene oxide (PEO)), or in PBS alone (as a control).

Prior to measurements in the tribometer, in all samples, the lenses werethoroughly rinsed by a stream of PBS. The lenses were then mounted onthe tribometer holder and friction forces measured while sliding againsta glass surface and immersed in PBS.

The glass substrates used were thin 24 mm×24 mm coverglasses (KnittelGlaser, Germany). They were removed from their pack (edge-handled withlatex gloves throughout), and glued into a standard 35 mm diameterpolystyrene Petri dish using Devcon® 5 Minute® 2-component epoxy. Justprior to the friction measurements, the upper glass surface was wipedwith an ethanol-moistened Kimwipes® tissue, then rinsed in de-ionizedwater to remove any ethanol traces, and the Petri dish then filled withPBS.

Dynamic light scattering (DLS) measurements showed that HSPC SUVs had adiameter of ˜100 nm, and DMPC SUVs had a diameter of ˜72 nm.

Friction coefficients were measured in PBS environment followingimmersion for two days in PBS per se or PBS solutions containing thetested liposomes (at a concentration of 10 mM) and/or the testedpolymers (0.2 mg/ml).

The applied loads (L) were 3 grams or 10 grams, and the correspondingmean pressures (P) are presented in FIGS. 4-7, respectively as L (ingrams)/P (in Atm units).

As shown in FIGS. 4-7, and in Table 1 below, immersion in DMPC (FIGS. 4and 6) or HSPC (FIGS. 5 and 7) liposome solutions resulted in asignificant reduction in the sliding friction coefficient μ of EtafilconA (FIGS. 4 and 5) and Narafilcon A (FIGS. 6 and 7) lenses relative tolenses immersed in PBS, in accordance with the results described inExample 1.

As further shown in FIGS. 4-7 and in Table 1, immersion inpolymer/liposome mixtures generally resulted in substantially higherreduction in sliding friction coefficients μ than did immersion inpolymer solution or liposome solution, especially at a load of 10 grams.

It is noted that all measurements were performed following 2-dayimmersion of the lenses in the tested solutions and a subsequentthorough rinse in a stream of PBS, such that subsequent measurementswere made in PBS alone. It is therefore assumed that there was no traceof free polymer or liposomes in the liquid surrounding the lenses in thetribometer. Thus, the results indicate an interaction and possibleattachment of the polymers to the surface of the hydrogel of the contactlens.

Without being bound by any particular theory, it is believed thatresults at a load of 10 grams are more representative of long-termlubrication effects than are results at a load of 3 grams.

As shown in FIG. 4 and in Table 1, PVP/DMPC liposome and PEO/DMPCliposome mixtures resulted in a reduction of 50% or more in the frictioncoefficients of Etafilcon A lenses in comparison with DMPC liposomesalone at a load of 10 grams.

As shown in FIG. 5, PVP/HSPC liposome and HA/HSPC liposome mixturesresulted in a reduction of 25-30% in the friction coefficients ofEtafilcon A lenses in comparison with HSPC liposomes alone at a load of10 grams.

As further shown in FIGS. 4 and 5, the abovementioned polymer/liposomemixtures resulted in a reduction of about 90% or more in the frictioncoefficients of Etafilcon A lenses in comparison with PBS or polymersolutions.

As shown in FIG. 6, PVP/DMPC liposome and HA/DMPC liposome mixturesresulted in a reduction of 22-40% in the friction coefficients ofNarafilcon A lenses in comparison with DMPC liposomes alone, and areduction of 50-72% in comparison with PBS or the respective polymersolutions, at a load of 10 grams.

As shown in FIG. 7, PEO/HSPC liposome, PVP/HSPC liposome and HA/HSPCliposome mixtures resulted in a reduction of 40-54% in the frictioncoefficients of Narafilcon A lenses in comparison with HSPC liposomesalone, and a reduction of 60-91% in comparison with PBS or therespective polymer solutions, at a load of 10 grams.

As further shown in FIGS. 4-7, mixtures of the non-ionic polar polymersPVP and PEO with liposomes resulted in at least as great a reduction insliding friction coefficients μ as did immersion in mixtures of theionic polymer hyaluronic acid with liposomes.

These results indicate that solutions containing ionic or non-ionicwater-soluble polymers and the liposomes resulted in frictioncoefficient values which were substantially lower than the frictioncoefficient values obtained for either component alone, thusdemonstrating a synergistic effect.

These results further indicate that SUV liposomes are highly effectiveat reducing friction coefficients (as are MLV liposomes described inExample 1) in combination the polar polymers.

As further shown in FIG. 4, a mixture of PEO and DMPC SUVs wasparticularly effective at reducing sliding friction coefficients ofEtafilcon A lenses, whereas PEO alone had no effect on the slidingfriction coefficient at a relatively low load (3 grams), and resulted inan increased sliding friction coefficient at a higher load (10 grams).

Similarly, as shown in FIG. 7, a mixture of PEO and HSPC SUVs wasparticularly effective at reducing sliding friction coefficients ofNarafilcon A lenses, whereas PEO alone resulted in increased slidingfriction coefficients.

These results surprisingly indicate a particularly strong synergy (atreducing friction coefficients) between PEO (which is not effective atreducing friction coefficients by itself) and liposomes of differenttypes, and on different surfaces.

TABLE 1 Friction coefficients of Etafilcon A and Narafilcon A contactlenses under different loads and mean pressures, following immersion inPBS solution with or without liposomes and/or a polar polymer(hyaluronic acid (HA), polyvinylpyrrolidone (PVP) or polyethylene oxide(PEO)). Mean Polymer in PBS Solution Lens Load Pressure Liposome NoMaterial (grams) (Atm) type polymer HA PVP PEO Etafilcon 3 0.1 No 0.21 ±0.055 ± 0.02 ± 0.2 ± A liposomes 0.07 0.01 0.005 0.02 DMPC 0.015 ± 0.012± 0.01 ± 0.009 ± liposomes 0.005 0.006 0.005 0.003 HSPC 0.016 ± 0.015 ±0.011 ± N.D. liposomes 0.007 0.005 0.003 10 0.16 No 0.28 ± 0.31 ± 0.11 ±0.45 ± liposomes 0.055 0.1 0.03 0.05 DMPC 0.024 ± 0.024 ± 0.012 ± 0.009± liposomes 0.007 0.008 0.004 0.003 HSPC 0.024 ± 0.017 ± 0.018 ± N.D.liposomes 0.009 0.005 0.003 Narafilcon 3 0.18 No 0.051 ± 0.025 ± 0.02 ±0.09 ± A liposomes 0.015 0.005 0.01 0.03 DMPC 0.015 ± 0.016 ± 0.01 ±N.D. liposomes 0.005 0.005 0.0035 HSPC 0.02 ± 0.018 ± 0.013 ± 0.012 ±liposomes 0.004 0.006 0.004 0.004 10 0.26 No 0.067 ± 0.05 ± 0.054 ± 0.12± liposomes 0.025 0.017 0.017 0.028 DMPC 0.032 ± 0.025 ± 0.019 ± N.D.liposomes 0.005 0.005 0.007 HSPC 0.033 ± 0.02 ± 0.016 ± 0.015 ±liposomes 0.008 0.01 0.008 0.006 N.D. = not determined

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

It is the intent of the Applicant(s) that all publications, patents andpatent applications referred to in this specification are to beincorporated in their entirety by reference into the specification, asif each individual publication, patent or patent application wasspecifically and individually noted when referenced that it is to beincorporated herein by reference. In addition, citation oridentification of any reference in this application shall not beconstrued as an admission that such reference is available as prior artto the present invention. To the extent that section headings are used,they should not be construed as necessarily limiting. In addition, anypriority document(s) of this application is/are hereby incorporatedherein by reference in its/their entirety.

What is claimed is:
 1. A method of reducing a friction coefficient of asurface of a contact lens, the method comprising rinsing and/orimmersing the contact lens in a solution comprising at least onewater-soluble polymer, liposomes, and an aqueous carrier, wherein anaverage molecular weight of said at least one water-soluble polymer isin a range of from 3 kDa to 10 MDa.
 2. The method of claim 1, whereinsaid contact lens comprises a hydrogel surface.
 3. The solution of claim2, wherein said hydrogel comprises a polymer selected from the groupconsisting of poly(2-hydroxyethyl methacrylate) and a silicone.
 4. Themethod of claim 2, wherein said hydrogel comprises a silicone.
 5. Themethod of claim 2, wherein said hydrogel comprises a polymer having nomore than one negatively charged group per 2 kDa.
 6. The method of claim1, wherein said at least one water-soluble polymer comprises a non-ionicpolymer.
 7. The method of claim 6, wherein said non-ionic polymer isselected from the group consisting of a polyvinylpyrrolidone and apolyethylene glycol.
 8. The method of claim 1, wherein said at least onewater-soluble polymer comprises an ionic polymer.
 9. The method of claim8, wherein said ionic polymer has from 1 to 6 charged groups per 1 kDa.10. The method of claim 8, wherein said ionic polymer is an anionicpolymer.
 11. The method of claim 10, wherein said anionic polymer ishyaluronic acid.
 12. The method of claim 8, wherein said liposomes arecharacterized by a surface charge having a sign opposite a sign of a netcharge of said ionic polymer.
 13. The method of claim 1, wherein said atleast one water-soluble polymer comprises a biopolymer.
 14. The methodof claim 13, wherein said biopolymer is selected from the groupconsisting of a mucin, a lubricin and a polysaccharide.
 15. The methodof claim 1, wherein a molar percentage of phosphatidylcholine in saidliposomes is at least 50%.
 16. The method of claim 1, wherein aconcentration of phospholipids of said liposomes in the solution is in arange of from 0.5 mM to 500 mM.
 17. The method of claim 1, wherein saidliposomes are selected from the group consisting of small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.
 18. Themethod of claim 1, wherein said liposomes comprise small unilamellarvesicles.
 19. The method of claim 1, wherein a viscosity of the solutionis no more than 1000 cP.
 20. The method of claim 1, wherein said carrieris an ophthalmically acceptable carrier.